Ideas? Small tricky progression, odd Guardant 360.

Brainstorming time! Please share anything you know that may help me think about possible treatment plans or good questions to ask, especially if you are familiar with genomic testing. Clues, thoughts, trials, research, educated guesses, snippets of info all welcome.

After two years of NEAD on Xeloda, two tumors have appeared. One is in the right lobe of the liver and measured 1.23 x .74 cm. The other one is in or near the common bile duct, and in July I got a temporary stent to treat the obstructive jaundice it caused. We biopsied the right lobe tumor and it showed the same old ILC: ER positive, Her2 negative. PR possibly negative (unlike original) but this result is uncertain. AR positive. Ki 67 15%.

Not enough biopsy tissue for genomics, so we did a Guardant 360 liquid biopsy. Now, two years ago the G360 test showed several mutations at low percentages, and one at a high percentage: an ERBB2/Her2 mutation at 17%. Suggested drug was neratinib. But we tried Xeloda first and I was quickly NEAD. So this time we expected the same Her2 mutation and talked of adding neratinib to Xeloda. However, this current G360 shows Not Detected for everything it found before: ERBB2, PIK3CA, RB1 (two of them), EGFR, BRCA1 (two of them) APC, TERT. Except FBXW7 went from .2% to .1% The medical liaison at Guardant told me that Not Detected can be caused by low tumor volume, low proliferation rate, and/or recent chemo — not a lot of DNA being shed. Two new ones showed up, but they are Variants of Uncertain Significance: BRCA2 at .2% and MET at .1%. MSI high Not Detected (so no Keytruda)

What to think?

Blame the two new ones and try a PARP inhibitor for BRCA2? Or Crizotinib for MET? I saw something here on BCO about a trial where Crizotinib would be offered if the patient's tumor had this mutation. Cf. The UK's ROLO trial for metastatic ILC which targets an apparently related gene, ROS1. Would I even be able to get these drugs for a VUS?

Assume that the ERBB2 mutation found two years ago could be at work and try neratinib?

Stay on Xeloda since it is controlling everywhere else and do local therapy on the two tumors as they appear to be rogue ones? I do not want rogue tumors to send out any minions. Liver/biliary guy mentioned microwave for the right lobe and standard radiation for the bile duct one. That sounds tricky with all the plumbing there, but we have a good IR.

Switch chemos? But Xeloda is mostly working.

The stent must be exchanged mid-October, unless we can get rid of or shrink the tumor before then.

P.S.Foundation One tissue biopsy from 2014 showed mutations in CDH1 (typical lobular) and TBX3. Also the MSH6 which is germline (Lynch). Variants of Unknown Significance in ARID2, BLM, CIC, NOTCH2, NTRK1, PIK3C2B, PRDM1, PRKDC, SPTA1. Foundation One and Guardant 360 do not look for the same set of mutations.

My oncologist is on vacation for two more weeks! I think she presented my case at tumor board but I have heard nothing about it. She said the standard medical oncologist answer was systemic therapy over local, but that is not the same as recommending against local therapy is it?

I would appreciate any input!

One option could be adding a second medication to Xeloda - either chemo or hormone therapy. However, some MOs only consider that further down the treatment road. I tried to get my MO to agree to that when I started having a bit of liver progression on Xeloda. He said no at the time (in 2016), as that was my 2nd line of treatment. Now that I am much farther along in treatment lines and beyond the obvious standard treatments (sadly), he is now on board with trying Xeloda again with another therapy added on as a future treatment.

Doing a local therapy and staying with Xeloda could be a good strategy too, or switching systemic therapy and doing local therapy.

If you do decide to go the IV chemo route, Doxil and Navelbine are not bad as far as side effects are concerned. Both very tolerable. I didn't have hair loss with either and cut out all premeds after the first or second infusion. Doxil is a 1-hour infusion given every 28 days (as it spends weeks circulating in the body undetected by the immune system) which is convenient. It is very targeted and most of the chemo only hits the tumor and, to some extent, the skin. Primary side effect is what I would describe as "fire feet" - a different kind of HFS than Xeloda. Navelbine is a 10-minute infusion or injection and is usually given 2 weeks on, 1 off. Primary side effect is a bit of very mild neuropathy, nothing like the taxanes.

I am of the opinion that Guardant is very sensitive to the amount of shedding. I had a Guardant test and it showed no mutations or abnormalities. However, I have numerous amplifications and mutations in the two F1 reports I have had. Even if the two tests do not test for the same thing, I find it hard to believe I have nothing abnormal on the Guardant test. I did the Guardant test when I was on Abraxane, when it was working. That may have been a mistake. Since Xeloda is mostly keeping your mets under control, there may not be enough shedding to be detectable at this point.

Hi shetland pony

I think when things get this confusing it might be time for a second opinion. You can look for a NCI hospital and they are set up to get to second opinions quickly. I had a wonderful experience through a clinical trial at Swedish Hospital in Seattle and they have multiple active studies. I wish you good luck getting the information you need to make a comfortable decision.

Thank you all for your responses. You are helping me to think this through and prepare to talk with my onc.

Cure-ious, the 2107 liquid biopsy did show two RB1 mutations. That was after about two years on Ibrance + letrozole — maintaining taxol NEAD the first year and slowing rising TMs second year until the scan finally showed the progression. I know abemaciclib can work even If Palbociclib failed, but do these details give you pause?

JFL, my onc was open to adding neratinib to Xeloda after I suggested doing that rather than using neratinib alone. So I think she would be open to adding some other therapy instead, unless the side effects from each look unsafe to combine. I'm not sure about a hormonal therapy because tamoxifen failed me after two or three years early stage, letrozole only seemed to work really well for one year (see above), and faslodex for four months worked not at all. On the other hand, I got to NEAD quickly on taxol and on Xeloda.

JFL and pajim, see, that's why I really wanted an F1 tissue biopsy again. I did F1 in 2014 from a breast biopsy — simultaneous breast and liver mets so we went for the easier one, though I know that is not ideal. This time, how could the IR take seven cores from my liver and only get one that had cancer in it? She is supposed to be really good but I wonder if she had studied the imaging enough beforehand, or if this is just the way it goes. Anyway, I figure a liquid biopsy does get around tumor heterogeneity, but it seems Guardant is not sensitive enough under my conditions. The medical liaison from Guardant thought not enough DNA was shed to detect mutations in this 2019 test and that it was worth considering the 2017 Guardant test results. So, can mutations that once were present go away? Or do they stay and more mutations get added? The ERBB2 was in the 2017 liquid biopsy, so it would not be a question of tumor heterogeneity. (I will PM you about the paper, pajim.)

I wonder if when they remove or change the stent (presumably in early October) they can try to grab some tissue for F1. I get the idea they would rather not because of infection risk. And I don't think they know if the tumor is inside or outside the common bile duct. Why don't they know?

BevJen, thanks for telling me what you learned about ROLO. My onc more than once over the years has mentioned obtaining what we need through compassionate use, so that is encouraging.

I have been thinking about doing as you suggest and trying to see the IR or RO next week, even before I see my onc. I don't want to break any etiquette rules — she is the orchestra leader — but I want to minimize the time it takes me to figure this out and take action.

3-16, this would be the perfect time for a second opinion. I tried in the past to get set up with a second opinion onc of my choice at another NCCN center in my state, but they kept asking me for more records, and then while I was getting those, more would be generated and I could not keep up. Eventually I dropped the ball. I hope she will still take me if I call again. But that will take time and require travel. It's hard to muster up the energy.

When I say that Xeloda is working everywhere else, I mean that when I was diagnosed metastatic, I had numerous liver mets and a breast met (yup), and now only these two show up. So far I have not been diagnosed with mets anywhere else, not even bone. So I think the cancer is making a fork in the branches; i.e. a new xeloda-resistant fork with the two current tumors. That is one reason I think local treatment makes sense. Kind of like oligo. Do you guys agree?

The other reason I want local control is that I don't want to mess with more stents. Even if other mets pop up, if we have gotten rid of the one so problematically placed, I will be in better shape. I really do need to consult the IR etc.

So is this what we have?

1. Local control if safe.

2. Stay on Xeloda alone if local treatment is done, or xeloda plus targeted therapy in either case.

3. If progression, go on a different chemo or a different targeted therapy.

Not sure whether to try and take a clue as to what therapy from any of the three genomic tests. If so, which one? 2014 test was tissue and more sensitive but it was breast not liver. 2017 test had a mutation at 17% which is high (ERBB2). 2019 test is the most recent and we could focus on the highest of the two VUS (BRCA2) if I would even be allowed to. Or just spin and point! I had hoped to individualize this more.

Thank you so much for reading my long post. It really helps me to discuss this with you and hear what you have to say.

Shetland, all your questions show the need for a second opinion- even to find out if you should just disregard this latest liquid biopsy and act on the previous one, while waiting for a new one? It would help to know why the cancer is endocrine-insensitive, and whether or not it is resistant to CDK4,6 inhibitors (ie if it is not Rb mutant, then Abemaciclib or CDK2 inhibitors could be used in the future; OTOH, for sure if Rb is mutated there is no point). And similarly, if the cancer does have a BRCA1-mutation, then add in a PARP inhibitor. I like the add-in something, rather than dumping Xeloda altogether, preferably waiting for more answers before switching to something new.. Good luck!!

My onc called. She recommended adding either taxotere or Halaven/eribulin to Xeloda. She said that there is data about combining these chemos with Xeloda. I hardly remember if she had a preference, but I do remember that she liked eribulin because at the recent ASCO conference someone showed it had a longer duration of response than some other chemos. I told her I would do taxol or abraxane but was not keen on taxotere, so eribulin it shall be.

She said tumor board had agreed that if the ERBB2 mutation showed up we should add neratinib. If it didn’t, they said switch chemos. She told them she did not want to drop Xeloda and showed them my past scans, how dramatic the response to Xeloda has been and how many tumors are still gone. That changed their minds about simply switching and they agreed with adding the second chemo to Xeloda.

Once eribulin has gotten rid of the tumor that was pressing on my bile duct (she says next to, not in), she wants to radiate that area to make sure it will stay gone.

She has two main concerns. First, how quickly the two tumors came up. So we don’t want to spend time experimenting with targeted therapies that may or may not be the right ones. Second, the bile duct stricture and need for a stent. Stents get infected often and she wants it out of there. So again, let’s move quickly.

She agreed to touch base with the medical liaison at Guardant, for my peace of mind.

Also, she is definitely open to a PARP inhibitor at some point. When they work, they can work really well.

So next week I will get my first Halaven infusion. Yikes, I did not really expect to be on two chemos at once.

Thank you, JFL; that is encouraging.