Progression After Truqap (Capivasertib) + Fulvestrant – Seeking Experiences and Next-Step Options

cure-ious

Hi Punam,

The study reporting the OS benefit is summarized in Ref 2 in my note above. Here is a link to the original article:

https://www.nature.com/articles/s41523-026-00965-6

In short, although the response rate to Keytruda was modest, and they got a PFS of only 3.2 month, nevertheless the overall survival benefit was great; 14 months for those with high TMB, vs 3.2 months for those without a high TMB. So there is a benefit to taking Keytruda for MBC patients, but only those with the high tumor mutation burden (I think they used 14 as a cut-off in this paper)

Based on that, you could argue that it doesn't help to use Keytruda right at the end, but rather try it in the middle and have something strong as backup

PS For local treatment of liver mets, Google indicates that there are two locations in Singapore that offer Histotripsy:

https://www.nccs.com.sg/news/patient-care/using-ultrasound-and-bubbles-to-destroy-tumours-new-cancer-treatment-to-be-trialled-in-singapore

In general, they prefer to treat tumors under 4cm, which is the size of the area that can be treated in a single session, but larger tumors can be treated by Y-90. Not all mets are in locations that are accessible to local treatments, but in principle this could be a fast and relatively easy way to reduce tumor burden should systemic treatments not keep everything at bay…

punam

Hi Curious,

Thank you so much for sharing the original paper and the information about histotripsy in Singapore. I really appreciate the time and effort you put into researching these possibilities and helping us.

I found the study particularly interesting. Although the progression-free survival was relatively short, the difference in overall survival among patients with ultra-high TMB is certainly encouraging. Your suggestion that Keytruda might be worth trying while Punam is still in reasonably good health, rather than leaving it until the very last treatment line, makes a lot of sense to me.

Punam's molecular results are also quite interesting. Her tissue TMB was 15.94 in December 2025, while her blood TMB around the same period was 34.86. A subsequent blood test approximately five months later showed a blood TMB of 65.48. Her tumour fraction also increased from 3.2% to 25.2% during that period. I understand that blood and tissue TMB cannot be directly compared, and that the increase in tumour fraction may influence the measured TMB.

She also has POLD1 variants, an ARID1A splice-site alteration, SETD2 Q109*, and BRCA2 single-copy loss. While the significance of some of these findings remains uncertain, I wonder whether their combination with the elevated TMB might offer additional clues about her potential response to immunotherapy.

We are awaiting another Guardant360 liquid biopsy report, which may provide further information.

I am particularly intrigued by your observation that immunotherapy might improve overall survival or responses to subsequent treatments even when the initial response is limited. I realize that the study does not necessarily establish this mechanism, but it is an interesting possibility and something I would like to understand better.

Regarding histotripsy, thank you for identifying the Singapore centres. We have already been in contact with the National Cancer Centre Singapore for an oncology opinion from Dr Rebecca Dent, so it may be worthwhile enquiring about their histotripsy programme as well. The main considerations would be suitability of the liver lesions, availability and cost. Given that Punam has multiple liver metastases as well as lymph-node involvement, we understand that systemic treatment remains essential.

At present, we are seriously considering Keytruda first, with Enhertu as a possible subsequent option. Our greatest hope is to achieve meaningful disease control while preserving Punam's quality of life.

Thank you once again for your continued interest, kindness and valuable insights. It is reassuring to have someone as knowledgeable and thoughtful as you sharing these ideas with us.

threetree

@punam - I don't know nearly all of the technical ins and outs of this like you and Cur-ious do, but just as a general observation from what I have seen and read, I think that trying Ketruda first would be a good idea.

Re the histotripsy - I had 10 lesions on my liver and had consulations with two liver specialists about a year ago. I turned out to not be a good candidate for histotripsy, not because of the number of lesions, but because they could not see them with ultrasound, and histotripsy is an ultrasound guided procedure. I saw one of the specialists to learn about more routine ablation like Y-90, and he told me he could ablate every one of those lesions, but that they were statistically very likely to come back, and that for all of the stress, pain, and trouble of the procedure and the necessary hospital stay, it likely wasn't worth it. This was from Raymond Yeung, MD at the University of Washinginton, in conjunction with Fred Hutchinson Cancer Center, an NCI designated place. My oncologist then said systemic treatment is what we would continue to look at.

The other doctor I spoke with was Mohamed Alassas, MD at Swedish Medical Center - a very well respected hospital and cancer center where they do histotripsy in my city. He too counted 10 lesions on my liver and explained the not visible on ultrasound issue preventing my being able to have the procedure. He told me that he knew the previous specialist I had spoken to about the ablation, and that he agreed with him about that probably not being worthwhile for me. As before, I have continued then with systemic treatment (Xeloda), and it has continued to work for me so far. I am trying to save Enhurtu "for last" . The part I want you to know most though, is that he and his staff told me that it is very possible to do some of both, i.e. both ablation and histotripsy, and that quite often the combination can be of benefit. That might be worth exploring too, along with systemic therapy.

Again, I do not have the academic and technical knowledge and expertise that both you and Curi-ous have, but I do try to chime in here every so often, with anything that I think might help.

I continue to wish both you and your wife all the best, and I truly hope that you can find a solution that works for a long, long time!

punam

Hi Threetree,

Thank you so much for sharing your experience in such detail. Please don't underestimate your knowledge. Firsthand experiences like yours, especially when supported by consultations with experienced specialists, are incredibly valuable to those of us navigating similar challenges.

I found your experience with histotripsy particularly informative. I hadn't fully appreciated how important ultrasound visibility is in determining whether the procedure is feasible. It was also interesting that both specialists independently felt that treating all the liver lesions might not be worthwhile because of the likelihood of recurrence.

Your suggestion about combining histotripsy with conventional ablation is certainly worth keeping in mind. Punam has multiple liver lesions as well as lymph-node involvement, so we recognize that systemic treatment remains the priority.

We are currently awaiting the results of another Guardant360 liquid biopsy, and her case is being presented to a molecular tumour board this Wednesday. Hopefully, these will provide some additional clarity and help us make a well-informed decision about the next treatment.

I am very happy to hear that Xeloda continues to work for you. Unfortunately, it did not work for Punam, but I sincerely hope it keeps your cancer under control for a very long time.

Thank you once again for your kindness, encouragement, and willingness to share your experiences. It truly means a lot to us. Wishing you continued good health and many more years of successful treatment.

threetree

@punam - Thank you so much for your very kind and uplifting words. I do hope that what I do know can help in some way. I think it's good that the tumor board will be meeting tomorrow to discuss Punam's case. That's another situation where multiple opinions and varied expertise can be a huge help. I hope that session ends with some very productive and hopeful possibilities for you. Please continue to keep us informed about how things are going. I agree with you that sharing all of these personal experiences amongst ourselves is one of the most valuable tools we have to to deal with this horrible disease. I continue to wish you all the best too!

punam

Thank you so much, Threetree, for your kind words and continued support. I am also hopeful that tomorrow's molecular tumour board discussion will bring some useful insights and promising treatment possibilities.

I will certainly keep everyone updated. I truly value the knowledge, experiences and encouragement shared in this community. They make a difficult journey a little easier.

Wishing you all the very best too!

punam

@cure-ious

@threetree

We met our oncologist today following a molecular tumour board discussion.

After progression on capecitabine, the board recommended starting Enhertu (T-DXd) for HR-positive, HER2-low (IHC 1+) metastatic breast cancer. They are considering adding Keytruda (pembrolizumab) off-label after the first cycle, depending on tolerance, because of the elevated TMB.

The molecular findings include:

• Tissue TMB approximately 16 mut/Mb; latest blood TMB approximately 21.5 mut/Mb.
• PIK3CA E545K and ESR1 D538G mutations.
• An NRG1 fusion detected in the earlier tissue biopsy.

The latest liquid biopsy showed a much lower ESR1 allele frequency (0.05%), but the tumour fraction was also substantially lower (3.1%) TMB going diwn to 25 from 65. The results were quite surprising since there was a definite progression in PET. Our oncologist contacted Guardant during the consultation, and they agreed to escalate the case for specialist review.

Our oncologist was of opinion that after almost ten years of treatment and several previous lines, future options may become more limited ineffective or difficult to tolerate. That was the reason the board suggested to throw the kitchen sink, adding keytruda to enhertu. I am however reluctant, since it can cause a toxicity issue. In any case we would be srarting Enhertu next week and after one or two cyckes shall review the descion on Keytruda.

The statement of oncologist had also created a sort of anxiety and we are a bit stressed because of it.

There are also some pre-existing mild ground-glass/fibrotic lung changes. The team plans CT chest monitoring every six weeks for ILD, particularly given the possibility of adding Keytruda.

I would really appreciate hearing from anyone with experience of Enhertu in HER2-low disease, especially after capecitabine, or anyone who has received Enhertu with immunotherapy.

I would also be interested in experiences with treatments after Enhertu, including other ADCs or newer endocrine combinations.

cure-ious

Hi Punam and Threetree,

After 11.5 years of treatments for metastatic ER+ cancer, this area you are discussing is my strongest interest, how do we best navigate into the future? No guideposts for where we are, and there are a lot of others like us, esp those like me, where the first CDK4,6 inhibitors had been approved just a few months before my diagnosis, so many are at the same point I am, with many more just a year or two behind me. We've made it far beyond the purported 3 year survival, and Her2-positive survival exceeds us, but how can we use the genomics and new trial drugs to get more out of life? The power of this forum is to crowd-source from those who may have found some more steps to a good quality and quantity of life after the standard of care options are finished. You raise interesting questions about histotripsy and immunotherapy and TMB, which we can follow up with shorter posts below.

cure-ious

Threetree,

Dr Kevin Burns in Mission Viejo Providence Hospital has been able or willing to treat multiple small mets in liver, and though they might not be well visualized by ultrasound, he does a CT overlay technique, and uses bits and bobs of liver, lets call it "junk" as roadmaps to align his mapping, as you can see in various clips on YouTube. It is a relatively new technique still, and one area that is improving is visualizing the treatment area; tho of course the mets can grow larger and then the technique is doable. But mets up under the ribs etc are just never going to be treated this way.

He published a report of a 30y/o patient who had been on many treatments and was currently on Enhertu, with 10 liver mets, which he treated with histotripsy in two different sessions, one for each liver lobe. He was not able to access all of each tumor, but hit what he could with the ultrasound, which has a 4cm aperture. The woman had a remarkable complete response, as seen in scans carried out in August and December of last year. Histotripsy is an out-patient procedure, done under complete anesthesia, and the results were exceptional given also that she was not taking immunotherapy. We cannot know how much of this benefit was due to the histotripsy, Enhertu, or the combination, but the outcome was as good as it gets.

The paper is here:

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2026.1782397/full

cure-ious

Histotripsy releases the cancer neoantigens (weirdo proteins the cancer makes that are not in regular cells) in an intact form, so it creates what is akin to a personalized vaccine in the liver that features the specific neoantigens of the person's cancer, and each cancer makes it own specific brew of these neoantigens). But the immune cells need help to access the tumors, which are covered with immunosupressive cells and hiding from immune attack. Immunotherapy is a monoclonal antibody that blocks some of this shielding of the tumor and lets immune cells access the tumor, so it should synergize with histotripsy to allow for better clearing out not just of tumors that were treated, but also other tumors in the liver.

Here is a recent clinical trial in the Netherlands where they are testing histotripsy with immunotherapy. The protocol they are using is to add the histotripy after the first cycle of immunotherapy.

https://research.umcutrecht.nl/news/histotripsy-and-immunotherapy-first-results-of-ifocus/

cure-ious

The other approach is combining immunotherapy with chemotherapy, and Hope Rugo will present at ESMO 2026 the results of a phase 3 trial (Keynote-B49) for ER-positive MBC where 800 people were treated with Keytruda and various kinds of chemo, at a point where the endocrine therapies have run out and they are just starting chemo regimens. They will be looking at the results based on whether the cancer has PDL-1 expression (and hence might respond to Keytruda). Most commentators aren't expecting great results, given multiple papers have shown that having PDL-1 expression is not sufficient to predict if someone will respond to Keytruda. It would have been much more helpful if they also looked at TMB, and maybe they can do that retrospectively. But at least it will be a starting point, ie what are the odds someone could benefit from just trying immunotherapy when they take chemo? They will look at overall survival, and that could be a surrogate for those with high TMB.

Of course one worries about the side effects of combining immunotherapy with chemotherapy, but Keytruda and Xeloda combinations are routinely used for those with triple-negative breast cancer, so maybe people here who have been through that can weigh in about that, but its even used for high-risk first line, so it must be tolerable.

cure-ious

Punam,

Thinking about the above trial, I wonder if Keytruda might not be sufficient, maybe the combo with Enhertu or another chemo is actually the better way to go? It seems Keytruda can take 2-4 months to fully kick in, whereas your wife needs treatment right away. Also, as you say the TMB is different in liver and blood, so maybe not all mets would be sensitive to Keytruda? Is it possible to try the combo for 3-4 months and then drop the Enhertu when scans show the tumors are shrinking or stable? Sorry that this is all so complicated.

punam

Hi Cure-ious,

Thank you again for your thoughtful suggestions. Your idea of using Enhertu for initial disease control while potentially allowing Keytruda to provide a longer-lasting immune response is very interesting, particularly given Punam's elevated TMB.

I am especially intrigued by your suggestion of eventually discontinuing Enhertu and continuing Keytruda alone if a good response is achieved. My only concern is whether Keytruda alone would be sufficient to maintain that response. I suppose there is no clear evidence yet, but it is certainly worth discussing with our oncologist.

For now, we are hoping Enhertu will provide good control of the liver and lymph-node disease while preserving her quality of life. We will carefully consider the additional benefits and risks of Keytruda.

Thank you also for sharing the remarkable histotripsy case. It is encouraging to see such outcomes, even though it is difficult to separate the contributions of Enhertu and histotripsy.

Thanks again for your continued interest and support!

cure-ious

Hi Punam,

Hopefully Enhertu works great by itself, and we just don't have much information about safety or efficacy of combining it with Keytruda. It sounds like both come with significant risks so it makes all the sense to start with Enhertu, she could get years on that alone! And it doesn't make sense to start with Keytruda monotherapy, as its a big question as to whether it would work anyway, and even if it did it would take months to find out. Please keep us updated about how this goes!