Progression After Truqap (Capivasertib) + Fulvestrant – Seeking Experiences and Next-Step Options
I am seeking experiences and suggestions regarding next-line treatment options for my wife with HR-positive, HER2-low metastatic breast cancer.
She has recently progressed on ibrance with exemestane then Capivasertib (Truqap) plus Fulvestrant, with PET imaging showing progression mainly in the liver and lymph nodes.
Molecular testing has identified a PIK3CA E545K mutation, ESR1 D538G mutation, NRG1 fusion, high tumor mutational burden (34.86 mut/Mb in blood and 15.9 mut/Mb in tissue), and somatic BRCA2 loss. PD-L1 CPS is 1.
Has anyone had a similar molecular profile or treatment journey? What treatment options were discussed with your oncologist after progression in a situation like this? Were there any therapies that worked particularly well or any options that you felt were worth exploring?
I would greatly appreciate hearing about your experiences and insights.
Thank you.
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Punam,
The Orserdu with Verzenio combination (ELEVATE) trial got very good numbers, PFS 14.3 months, this is what I am trying after just completing a clinical trial for a PIK3CA mutation. The PIK3CA mutations cause the cancer to become resistant to endocrine therapy, but now that we knocked down the mutation on the trial, I want to see if the cancer will respond yet again to Orserdu + CDK4,6i. The oral SERDs for ESR1 mutation can work on PIK3CA mutant cancers, but the response isn't as long as they see with the wild-type PIK3CA kinase.
The high tumor mutation burden makes it interesting to try immunotherapy; my cancer is also high TMB but opposite to that of your wife (ie, 39 in tissue but 15, in blood), however I will try all the endocrine therapy options before trying immunotherapy. Other endocrine options are Girdestrant with Everolimus, which also did well in trials and is submitted to FDA, as well as combinations with CDK2 or KAT6 inhibitors. Some studies indicate ER-positive or ESR1 mutant MBC won't respond to immunotherapy unless you block the estrogen signaling, ie, you'd want to be taking Orserdu/oral SERDs or Faslodex along with Keytruda. CDK4,6i also strongly boost response to immunotherapy in preclinical studies, however in human trials they found that the combination of Keytruda + anti-estrogen + CDK4,6i was too toxic.
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@punam - I have been in a somewhat related situation, so maybe some of what I can offer will help. In no way can I give you as detailed and as academic a response as Cur-ious did. She's excellent with the research and explanation of things!
I was diagnosed in the fall of 2018 with ER+, HER low, stage 3b breast cancer. In January of 2023 I was told I had mets to my bones, so became stage 4. I began Fulvestrant and Verzenio that spring. Around the fall of 2024 radiology reports began to note a spot or two on my liver, but the growth was so slow, my oncologist kept me on the Verzenio/Fulvestrant combo and we "watched and waited" re the liver issue. As time went on the liver issue slowly got bigger, and I wound up consulting with two different liver surgeons re possible treatments they could provide. They both said that anything they might do would be essentially futile, because the liver mets would just return even if they were able to ablate them (by then I had 10 lesions on my liver). During that same time, it was discovered that I had the ESR1 mutation and an AKT1 mutation. The Fulvestrant and Verzenio combination were no longer working, but progression remained slow. Last fall I began to feel a bit worse and new mets began to show on both my bones and liver, so the doctor felt it was time to move to the next line of treatment.
My oncologist and I then talked about Truqap and Xeloda as being next line possibilities (this was fall of 2025). I said something to him about possibly trying Xeloda next, due to things I'd read about efficacy and side effects, etc. He said we should go with Truqap first, and then Xeloda. Well, at some point, he decided that due to my getting a lot of side effects from most drugs, we might just skip the Truqap altogether, so we did, and I began Xeloda in January of 2026. So far things have been going well. My tumor markers are down into the normal range now, my bone mets seem to have "healed", and the liver mets can no longer be seen on scans. I am assuming that Truqap could still be a possible option down the road if and when the Xeloda stops working,
I have never had a PET scan, and have only ever done CT's with and without contrast, nuclear bone scans, and MRI's.
You might want to consult with some liver surgeons and give the Xeloda idea some thought.
This was a very condensed version of my experiences so far, but I didn't want this to get too long. I'm truly sorry that your wife is going through this, and I think it is wonderful of you to do this research and find out what you can for her. Wishing you both lots and lots of luck!
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3Tree brings up an excellent point, in that other non-endocrine approaches can still be used on tumors with PIK3CA mutations. And because there are a group of PIK3CA mutant-specific drugs that are currently working their way thru Phase 3 trials, which are more effective and have far fewer side effects than Capivasertib, starting with Xeloda or Enhertu instead might be a good way to go for now and plan to hit the PIK3CA mutation further down the road!
Regarding histotripsy, about 90% of those treated tumors are not back within a year, and many patients have gone years without them returning, the histotripsy opens up the tumor shielding microenvironment and gets rid of the hypoxic environment to let the immune system clear out the treated tumors more effectively. And if the same tumor does appear again it can be re-treated with histotripsy, which is not true for radiation. But of course, it is not a cure, and the liver will still have micromets that can and will grow if the patient is not on an effective systemic treatment. Also, local liver treatments can be combined, for example histotripsy can be used for partial ablation of a very large tumor, giving a strong immune "vaccination" effect that then can synergize with subsequent Y90, where the tumor is hit with radioactive beads hitting the tumor by y90. Its just that these treatments aren't normally used until the tumor burden or size gets too much, or if there are just one or two tumors that are resisting treatment and those can be zapped so the therapy can continue.
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@ cure-ious Thank you very much for your detailed and thoughtful response. I truly appreciate the depth of knowledge and research-based guidance you share on this forum. It is extremely helpful for families like ours trying to understand complex treatment choices.
One additional consideration is that we are based in India, where access to some newer drugs like Orserdu, Inavolisib, clinical trials, histrotripsy and off-label treatments may be more limited than in the US or Europe. Therefore, I would be particularly interested in options that are commercially available, realistically accessible internationally, or potentially obtainable through compassionate-use programs.
Our oncologist has also mentioned the possibility of off-label Afatinib because of the NRG1 fusion. My wife also had an ischemic stroke in 2024 with residual right-sided weakness, so treatment tolerability and vascular risk are important considerations. A very low-frequency RB1 mutation (~0.1–0.2% VAF) was detected on liquid biopsy. The maximum frequency was fir Setd2q109 followed by PIK3CA E545K. So it was really a setback that Teuqap didn't work.
Given the ESR1 mutation, PIK3CA mutation, high TMB, NRG1 fusion, prior stroke, and progression after Truqap + Fulvestrant, I would be very interested in how you might prioritize the available options and what sequence you would consider most reasonable.
Thank you again for sharing your experience and insights.
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@threetree Thank you very much for sharing your experience in such detail . It is encouraging to read that Xeloda helped bring your tumor markers down and that the liver lesions are no longer visible on scans.
Your point about slow liver progression and discussing both systemic treatment and possible liver-directed approaches is very helpful. We will certainly discuss Xeloda and the overall treatment sequence with our oncologist.
Wishing you continued good response and good health. Thank you again for taking the time to share your journey.1 -
@cure-ious. You mentioned that with PIK3CA mutation endocrine resistance is developed, but our case was a bit different. Even after developing this mutation Palbociclib and Exemestane worked a long way. Although strangely its inhibitor Truqap didn't work.
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@punam - I agree with you completely that cure-ious brings us much appreciated "detailed and thoughtful" responses. I always welcome what she has to say.
Given what I understand, I think I would ask the oncologist about Xeloda, Enhurtu, and "liver directed therapies" for whatever they might be worth. While both of the liver surgeons I consulted with indicated that those therapies wouldn't particularly help me, they can help others, but from what they said, breast cancer is unique in that "liver directed therapies" and sometimes even histotripsy, just don't work, and the lesions come back almost all the time. They cited collective statistics and said that some will do well with these therapies, but that the overwhelming majority will not. Also, as Cure-ious noted, you can try a combination of all sorts of these different liver therapies and what won't work on one, might work on another, e.g. you can do ablation on some lesions, and histotripsy on others. The liver specialists I consulted with felt that most of this was not worth it for breast cancer patients, due to the facts that the procedures themselves can be difficult, and the time spent in the hospital and recovering, can take a good while and be unpleasant. They felt that to go through all you have to go through with the liver treatments, just to most likely have them come back in a relatively short period of time, wasn't worth it for most patients.
That said, there are a number of people on these threads who had one or maybe less than a handful of lesions, and they did OK with the ablation, etc. It seems to be the multiple lesion situations that are much trickier. I asked my oncologist about the fact that while the lesions would likely return in these cases, somebody's lesions would return in 2 months, but somebody else's might not return for 2 years. He agreed, but said exactly what one of the surgeons said, i.e. that "no one has a crystal ball" unfortunately. They can only go by the collective statistics. (Additionally, where histotripsy is concerned, the lesions have to be visible on an ultra sound, as it is an ultra sound guided procedure. Apparently the lesions can sometimes acquire the same density as the liver itself and cannot be seen, so cannot be treated, as in my case.)
I appreciate that you do not have access in India, to all of the different treatment possibilities that are out there, so what I'm suggesting is just what I know, as I don't know exactly what might be accessible to you where you are. I can also appreciate your disappointment in Truqap. I have noticed in reading these threads that Truqap doesn't work very well for many. It seems that a lot of people get a few weeks or months with it, but nothing longer term like you can get with some of the other drugs. I have though seen where a few have had more long term success with Truqap, but I don't think it's the norm, and it apparently comes with a lot of side effects, some of which can be rather dangerous. I truly believe there is something out there that will help your wife, and that if you just keep asking searching and asking questions, you will hit on the right next step. I'm sending good thoughts and wishes your way. Take care.
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@threetree Thank you once again for taking so much time to write such a detailed and thoughtful reply . I truly appreciate the effort you have made to share not only your experience but also the discussions you had with your oncologist and liver specialists. For someone trying to understand a complex situation, insights like yours are incredibly valuable.
Your comments regarding liver-directed therapies were especially helpful. It is useful to hear both the potential benefits and the limitations from someone who has explored those options in depth.
I am also very encouraged by your experience with Xeloda. Reading that your liver lesions are no longer visible on scans gives hope that meaningful responses can still occur even after progression on earlier treatments.
We have now managed to secure an appointment with Dr Rebecca Dent at NCCS Singapore for an additional opinion, and a repeat liquid biopsy has also been sent, with results expected shortly. We are hoping that the additional molecular information may help guide the next treatment decision.
Thank you again for your kindness, generosity, and encouragement. Wishing you continued good health and a long-lasting response to treatment.
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@punam - Yes, I back up everything threetree is saying, seek out experts, explore trials and look for new regional centers that might be able to help, as you are doing in Singapore! And when you find someone there to help, it will get easier to come and go for help and advice when needed. Histotripsy looks wonderful but of course there are also limitations, not every liver met is accessible, many are not, and others might only be partially ablated. In terms of alternatives for large or inaccessible resistant tumors, Y90 radioembolisation has gotten some very favorable reviews on this site.
but also histotripsy can be useful for generating a personalized vaccine with intact neoantigens to improve the response to immunotherapy, and any liver met they can hit would work well for that function. The ASCO 2026 meeting indicates that GLP-1 drugs might be a large benefit for helping immunotherapy to work, first by switching pro-tumor macrophages to anti-tumor macrophages and in that way open up the tumor microenvironment, and also prevent exhaustion of NK and T cells, and on top of that can protect against some of the worst side effects of the immunotherapy drugs like Keytruda. So adding a GLP-1 drug to the anti-cancer drug regimen might be a good idea when using histotripsy to boost an immune response.
Whether the goal is to remove one or a few large or drug-resistant liver mets, or to debulk the liver following a bad progression, or to help a response to immunotherapy, its worth trying to find a regional cancer center that offers this procedure ( and the number of places offering this is increasing fast) and go ahead and get signed up at that hospital and consult the local MO, to get everything ready in case one needs help quickly at some point in the future.
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@cure-ious - Very interesting about the GLP-1 drugs figuring into breast cancer therapy. This is the first time I've ever heard about that, and will look forward to hearing and learning more, as time goes on. Thanks as always, for some very interesting information.
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@cure-ious Thank you again for sharing your knowledge and research insights . I had a few additional questions that I would be very interested in hearing your thoughts on.
The tissue report mentions BRCA2 loss/copy number around 1.2, but this is not a germline BRCA mutation and was not clearly reported on liquid biopsy. Do you think such a tissue-only BRCA2 loss has any meaningful relevance for considering PARP inhibitors such as Olaparib, or is it usually not enough?
Also, given progression on Capivasertib despite the presence of a PIK3CA E545K mutation, would you still see a potential future role for Inavolisib or other next-generation PIK3CA-directed therapies?
Finally, one finding that has particularly intrigued us is the NRG1 fusion. Our oncologist briefly mentioned off-label Afatinib as a possible consideration. In your view, how actionable is NRG1 fusion in metastatic breast cancer, and would Afatinib or any NRG1-directed approaches be worth exploring?
I would greatly appreciate your perspective.
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@threetree Thank you again for taking the time to share your experience . Your comments have been extremely helpful and encouraging.
One additional factor for us is that my wife had an ischemic stroke in 2024 with some residual right-sided weakness, so preserving mobility and overall quality of life is especially important when considering future treatments.
Since you have done so well on Xeloda, I was wondering if I could ask a practical question. How has your quality of life been while taking Xeloda, and have dose adjustments or alternative schedules (such as 7 days on / 7 days off) ever been discussed by your oncologist?
One of our biggest concerns is finding a treatment that can provide disease control while still allowing a good quality of life, so hearing real-world experiences is extremely valuable.
Thank you again, and I wish you continued good health and a lasting response to treatment.
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Punam, I don't know about the BRCA1, it seems iffy?
For PIK3CA, definitely look for the mutation-specific drugs (RLY-2608; STX-478; SNV4818) but you probably want to wait for the PIK3CA mutant cells to grow back up, since you just knocked a bunch of them down with the Capivasertib. And if any of the oral SERDs ever get approved for ESR1 wild-type cancers then that would be a new and stronger combination than the Faslodex-Capivasertib.
For NRG1 fusion, it seems this can definitely be a driver, and there are multiple drugs, the Afatinib you mention as well as monoclonals that might be worth asking about: https://pmc.ncbi.nlm.nih.gov/articles/PMC11878197/
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@cure-ious Thank you very much for taking the time to look into this and for pointing us toward the PIK3CA-specific agents and the NRG1 literature . Your comments are extremely helpful.
Your observation regarding NRG1 fusion is particularly interesting because it was one of the findings that caught our attention as well, and our oncologist briefly mentioned off-label Afatinib as a possible future consideration. We have also managed to secure an appointment with Dr Rebecca Dent at NCCS Singapore next month, so NRG1-directed approaches will definitely be one of the topics we discuss.
The idea that future PIK3CA-specific agents might still have a role despite progression on Capivasertib is also encouraging and gives us another avenue to explore.
Thank you again for sharing your knowledge and for helping patients and caregivers navigate these complex decisions.
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@punam - I am very sorry to hear about your wife's previous stroke. While we are all concerned about quality of life with treatments, I can see why it is of very high interest to you.
As with all treatments I do have some quality of life issues with Xeloda (fatigue in particular), but all in all, it has been "doable". I also have some lightheadedness and subsequent balance issues from time to time, and with a prior stroke, that could be an issue for your wife, but I don't believe an insurmountable one. I take 3000 mg a day in two divided doses, and I am on the 7 on, 7 off, schedule. My oncologist put me on that schedule because of my tendency to have problems with side effects from most any drug, and due to a study from 2025 that he cited about how those who did 7/7 did just as well or better than those on the traditional 14 on, 7 off, regimen. From what I have heard from others on the Xeloda thread, most prefer the 7/7 and find that their side effects aren't as bad with that. Fortunately, over the six months that I have been on this drug, I have not had the diarrhea, nausea/vomiting, or hand foot issues that others can have, outside of a little reddening on the palms and fingers of my hands, and soles of my feet. I feel very fortunate at this point to only have the few issues that I do, although the fatigue is quite notable. I strongly believe that my lack of any real digestive problems is likely due to the fact that I eat fresh probiotic sauerkraut every day at lunch, and then in the afternoon I have full fat plain Greek yogurt (usually with fruit and nuts added).
My oncologist has suggested the possibility of a lower dose if my results continue to look as good as they have been. I see him tomorrow and might bring that issue up, although I am wary of rocking the boat, even though I'd like to have fewer side effects. Many here who take or have taken Xeloda have had dose reductions with success although one I read about indicated that she had had a reduction, but then progressed, so went back up to the 3000 mg.
I hope this is of some help to you and your wife. I absolutely agree with you about the value of "hearing real-world experiences". That is just about 100% of the reason that I use this site. The experiences I hear about from others are priceless.
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@threetree Thank you very much for such a detailed and thoughtful reply . I truly appreciate the time you took to share your experience.
Your comments regarding the 7 days on / 7 days off schedule, quality of life, and side-effect management are especially helpful. It is also encouraging to hear that despite some fatigue and balance issues, you have found Xeloda to be manageable overall and that your liver lesions have responded so well.
Thank you as well for your kind words regarding my wife's stroke. Quality of life is indeed one of our biggest concerns, and hearing real-world experiences such as yours is invaluable as we navigate the next treatment decisions.
I am very grateful for your generosity in sharing your journey and wish you continued good health, stability, and a long-lasting response to treatment.
With sincere thanks.
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@punam - You and your wife are very welcome. Please don't hesitate to ask if there is anything I might be able to do to help. I want your wife too, to have a good and long-lasting treatment! She is very lucky to have you doing all this research and caring so much. My absolute best to the both of you.
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Thank you again for the shared experiences and guidance. After discussion with our oncologist and an additional specialist opinion, my wife has now started Capecitabine/Xeloda on a 7 days on / 7 days off schedule, 3000 mg per day in two divided doses.
We are now focusing on tolerability and side-effect prevention, especially hand-foot syndrome, fatigue, diarrhea, and mouth ulcers.
Pl let ys have practical tips for managing Xeloda on a 7/7 schedule, especially during the first few cycles, I would be very grateful to hear them.
Thank you again for your kindness and support.
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@punam - I'm very glad to hear that you have seen some specialists and are making some progress via starting the capecitabine. I have my fingers crossed that it will work long and well for your wife.
I will get back to you again, when I can, but I have pulled some muscles in my back and chest, unfortunately, and typing can cause muscle spasms and more. I would love to share some personal tips with you, but it will have to wait. In the meantime, in case you haven't already found it, you might find a lot of good information here at the Xeloda thread: There are lots of ideas there like Metamucil for diarrhea, "Udderly Smooth" cream for hand/foot syndrome (along with many other possible creams), info about folate and it's interaction with the drug, etc.
https://community.breastcancer.org/en/discussion/772113/all-about-xeloda#latest
Again, I'm really sorry that I can't share more right now, but I am only able to make short brief comments, if at all, on these threads for now. Please know that I am thinking of you and your wife and will check in again when my muscles have healed. I'm getting a PT referral, as I've heard this can take a long time. Please take care and know that many of us are thinking of you and your wife and want to help.
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@threetree Thank you very much for taking the time to reply, especially when you are dealing with your own pain and muscle spasms. Please don't feel any pressure to write more right now. Your health and recovery are far more important.
I truly appreciate all the guidance and encouragement you have already shared. Hearing about your own experience with Xeloda and your thoughtful explanations has been extremely helpful to us while making treatment decisions.
My wife has now started Xeloda on a 7 days on / 7 days off schedule, and we are hoping for both good disease control and good quality of life. I will certainly go through the Xeloda thread and read the practical tips you mentioned.
Thank you again for your kindness, generosity, and support. Please focus on your recovery, and I hope the physical therapy helps you feel better soon.
Wishing you continued healing and good health.
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Hi Putnam I trust that your wife is doing ok on Xeloda. I am also new to this med but in my 10th year with metastatic breast cancer and 22 years from breast cancer Dx. I too am on 7/7 and now in my 3rd week of 4. I am a vegetarian and so was very concerned that folate may cause me lots of s/e. However I have continued with my normal diet but cut out all added folic acid and so far no hfs or mouth sores. My husband and I check everything and this means many breads, biscuits, cakes etc are out. I enjoy lots of sweet things however we have found alternatives and life goes on.
I wish you both good luck and hope Madam X works for us for a long time.1 -
@chico Thank you very much for sharing your experience. It is encouraging to hear from someone who has been living with metastatic breast cancer for so many years and is also using the 7/7 Xeloda schedule.
My wife has recently started Xeloda and we are still in the very early days, so hearing about real-world experiences is extremely helpful. I appreciate your comments regarding folate and dietary considerations, and we will certainly pay attention to supplements and food labels.
Most importantly, it is reassuring to hear that you have not experienced hand-foot syndrome or mouth sores so far. We are hoping for good tolerability and a long response as well.
Wishing you continued success with "Madam X" and many more good years ahead.
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