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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