Case 4

Dr. Matthew Goetz:

We're going to move on to another case. This is another case, a patient in the metastatic setting. And this is a patient who presents with a late recurrence of breast cancer. This is a 61-year-old female. She was originally diagnosed in 2002. She presented at that time with a clinical stage II ER/PR-positive, HER2-negative breast cancer. She was treated with lumpectomy and postoperatively, she was found to have disease within the breast. She had one involved lymph node as well. And because of this, this was prior to obviously the time when we were utilizing multigene assays for decision-making, but essentially, we're making decisions based on information about age and clinical stage. She received AC and docetaxel and then received adjuvant radiation therapy to the breast. She received 5 years of tamoxifen and this was completed in November 2007.

And at the time, she was offered extended adjuvant hormonal therapy with the drug letrozole based on the results of the MA.17 clinical trial, which demonstrated the benefit of extended adjuvant letrozole, but she had some difficulties tolerating it. So essentially she, received 5 years of adjuvant endocrine therapy. Ten years later, in 2017, she came to her local physician with a chronic cough, shortness of breath and weight loss. And she was referred to me at that time because there was concern about a late recurrence of breast cancer. And interestingly, this particular patient actually had a fairly aggressive presentation. She presented with a very moderate to large pericardial effusion and there was pericardial tamponade that was seen at least by echocardiogram even though she didn't have it clinically. She did undergo a pericardiocentesis and this confirmed the diagnosis of breast cancer, late recurrence, ER-positive, PR-negative, HER2-negative. Her staging workup was completed.

She had a PET scan, she had FDG-avid bilateral hilar mediastinal lymphadenopathy extending into the neck. She had multiple FDG-avid skeletal lesions and she came to our institution and was enrolled in a prospective tumor sequencing study. This particular study utilized the standard of care at that time, which was palbociclib and letrozole. I'm going to stop there and again, we're going to put on our hat, this was 2017. And Kevin, your thoughts and we talked about a premenopausal patient earlier. This patient is now presenting to your office today. Some might even call this some type of visceral crisis, although the short-term crisis has been taken care of because she no longer has the tamponade. Your thoughts about treatment for this patient.

Dr. Kevin Kalinsky:

Yeah. I mean, one, I think this case highlights just how frustrating late recurrences can be, right? You have a patient who's 10 years out, you hope that she could be out of the woods and then has a distant recurrence. I think this area of ongoing investigation is how can we best prevent late recurrences and the conversation that we had in terms of case 3 with SERDs and potentially SERMs, right? This question of whether we can further optimize the endocrine therapy in the adjuvant setting to prevent these late recurrences remains an important question. I think that if we were to be seeing this patient in our clinic now, I do think that I would be thinking about ribociclib for this patient as opposed to palbociclib.

But I also think this particular case is highlighting that you can see significant responses with hormonal therapy and a CDK4/6 inhibitor, right? Response rate that can exceed 50%. And we had historically, for patients who we were concerned about, thought about initiating chemotherapy for these patients. And I will say my practice pattern has really changed since these agents came out because you can see nice, durable responses with the combination of endocrine therapy and a CDK4/6 inhibitor.

Dr. Matthew Goetz:

Yeah, thank you very much. It's I think a true delight from my standpoint to be able to offer patients oral therapy that generally is well tolerated, that achieves response rates that are very comparable historically to what we gave with doublet chemotherapy. And so this really has been a major improvement for patients. And I agree like you that this patient would normally, well, I would say in 2022, based on the data that we're seeing, we would utilize ribociclib along with an AI in this particular situation.

Sara, this patient did undergo tumor sequencing and she of course was treated with palbociclib and letrozole. And shortly after getting the tumor sequencing, she was found to have a p53 mutation, several PIK3CA alterations that were considered to be pathogenic, as well as PTEN loss. Would any of these findings change how you would've treated her? Let's say you had that information right upfront, right even before you started treating her, would that have changed in any way how you treated her or how, in this case, the choice of CDK4/6 inhibitor versus something else?

Dr. Sara Chumsri:

Yeah. So I think with the PIK3CA mutation, it's in the first-line setting, it's more kind of like a prognostic rather than predictive per se. I think with apelisib and the SOLAR-1 data, I normally choose that as the second line. It's also because of the risk/benefit ratio, the toxicity of the CDK4/6 inhibitor. As Kevin was mentioning, you can get a really high response rate and alleviate a visceral crisis with just the CDK4/6 inhibitor. With the PIK3CA mutation and alpelisib, it's more difficult with the side effects profile and everything. And I normally choose that for a second-line treatment based on the SOLAR-1 trial, so I would not change the management, I would go with the CDK4/6 inhibitor in the first-line setting and then save the alpelisib for the second line.

Dr. Matthew Goetz:

Great. So this particular patient had treatment, again, with palbociclib and letrozole. She tolerated therapy relatively well. One of her main symptoms was a cough and some shortness of breath, and a lot of those symptoms really stabilized after her pericardiocentesis, although she still continued to have some cough. And with therapy, her cough did improve some and unfortunately, after about 7 months of therapy, imaging demonstrated disease progression within the bones, but there was improvement within the chest.

So Kevin, sometimes, we see these cases in our clinic where I like to say it, maybe it's a bit of equipoise where maybe there's just one lesion that's changed and the patient is otherwise tolerating therapy well, there's some symptomatic improvement. Sometimes, some people use it as spot welding, radiating one lesion and then continuing therapy. Do you restrict that idea to only if it's symptomatic? What would you do in this situation if, let's say the progression was, there was some equipoise?

Dr. Kevin Kalinsky:

Yeah. So one, I will say if you have a patient with metastatic disease, you start their hormonal therapy often with a CDK4/6 inhibitor and then you do the next set of scans. It's not infrequent that we'll see some new lesions that we might not have seen before. And it's just to reiterate, it's important to hang tight, right? Because there may be just some of those lesions may be healing, like for instance on a CT scan, you may see something where something's more sclerotic and that may be a healing process as opposed to actual progression. I will say that I tend to, if I'm seeing any progression in any location, I tend to be conservative and that I often, given the fact that we have multiple agents available for these patients, I tend to make a switch. I will say if I had a patient who was having some isolated bone discomfort but had significant visceral disease and I felt like things were really under control, giving a little bit of radiation and seeing how she does is entirely reasonable, but I think it really is a bit of a patient-dependent scenario.

Dr. Matthew Goetz:

Great. This patient, unfortunately again, after 7 months, did develop progression and in this case, the progression, the bone was really not equivalent. There was really clear evidence, there were multiple new lesions, and I recall at the time, we had a discussion with the patient about the use of a PI3 kinase inhibitor. We actually had a clinical trial available versus, by the way, the treatment with alpelisib, which was not quite yet FDA-approved at that point. And so she was treated, by the way, with capecitabine and I was hoping she would get a very good response to capecitabine, but unfortunately, she rapidly progressed. She developed within a very short period of time, 4 months, symptomatic progression in her bones, soft tissue, and liver. And interestingly, when this occurred, she also ended up developing an acute kidney injury, secondary to urinary obstruction, and actually ended up requiring bilateral stent placement.

And I remember at the time when I saw this particular patient, I went, dug back and went back all the way to the original diagnosis in 2000 and in 2001 or 2002 when she was diagnosed. And indeed, she did have a mixed mammary carcinoma, so she had both lobular as well as ductal components. And in my mind, this seems classic for potential for retroperitoneal and/or peritoneal involvement.... The lobular cancer leading to this finding, which otherwise by the way, was fairly unusual, urinary obstruction requiring percutaneous stent placement. Sara, have you seen this much with lobular breast cancer? This was as an unusual situation that I saw with this patient. Is this something you see?

Dr. Sara Chumsri:

Yeah, I do see patients with lobular carcinoma who present with this metastatic disease in the peritoneum. This case actually brings up a case I previously published that looking at tumor mutational burden and APOBEC mutagenesis. What we found is that patients who had invasive lobular carcinoma, up to 18% actually, may have APOBEC signature that cause hypermutation in the tumor. The APOBEC signature also correlate with the PIK3CA mutation, certain site in the PIK3CA, actually the site for the APOBEC. And I had a patient who had a similar finding that she actually progressed rapidly through endocrine therapy, chemotherapy, and then we did the NGS on her.

 

And besides these, like PIK3CA mutation and other things, she was also found to have high tumor mutational burden. These mutations usually in a high 40 to 70 mutation per mega base rather than in the low, in 10 or 20, something like that. And my patient actually responded really well with the immune checkpoint inhibitor, with now pembrolizumab being approved for patients with high tumor mutational burden. Something to think about. I think we do see those more in patients with invasive lobular carcinoma.

Dr. Matthew Goetz:

Great, thank you very much. It's really quite fascinating. I think as we're learning more and more about the lobular subtype of breast cancer, we're learning not only about some of the unique mutations that maybe target all, obviously, the HER2 mutations have received a lot of press, but also as you point out your very interesting findings with regard to APOBEC and this hypermutation spectrum. Kevin, in this situation, this particular patient also, I don't have it listed here on the slide, but also presented with pancytopenia in the midst of all this as well. And we did a bone marrow biopsy and found extensive infiltration of her bones with breast cancer, we think, as at least contributing to the pancytopenia. So, a patient like this presenting with now progression on a CDK4/6 inhibitor, progression on capecitabine and now with fairly substantial progression, bone/liver leading to cytopenias, what are your thoughts about next steps and how would you approach this patient?

 

Dr. Kevin Kalinsky:

Yeah, I mean for this particular patient, one, this is a challenging scenario, right? Because the only way the cytopenias are really going to improve is if you get the disease under better control. And this is where I always opt to intravenous treatments. I think weekly Taxol is an entirely reasonable thought for this particular type of patient, just given that it's not terribly myelosuppressive. I also think what would be interesting for this particular patient now would be whether she had a HER2-low tumor because this is the scenario where if she were HER2-low, based upon the DESTINY trial, one could consider utilization of trastuzumab deruxtecan as well.

Dr. Matthew Goetz:

Yeah, that's a fascinating comment and I think we are, all of a sudden, going to be rethinking about how we might approach some of these difficult patients because we have drugs that are really more active. And maybe you could comment a little bit about trastuzumab deruxtecan, the DESTINY study, the recent FDA approval. What about cytopenias with trastuzumab deruxtecan? Is that something we have to be concerned about in this situation?

Dr. Kevin Kalinsky:

Yeah, it can be, I think in particular neutropenia. I think that's one thing we'd have to really monitor, but I think the other thing is that you can see really nice responses and of course, in DESTINY-Breast04, we saw the comparator versus chemotherapy and those chemotherapies had included taxanes. So I think that you can see some really significant responses, but it is that this is the one thing for this particular patient really to be mindful of, is just monitoring blood counts.

Dr. Matthew Goetz:

Great. And another thing of course, Kevin and Sara as well, that we were seen this very intriguing data with regard to the antitumor effects of trastuzumab deruxtecan and its potential penetration into the brain in brain metastases, in tumors that are HER2-positive. Do we have any data at all in HER2-low, ER-positive, HER2-low breast cancer with brain metastases? Have you seen any data there?

Dr. Kevin Kalinsky:

None that come to mind, but the data that we've seen in HER2-positive disease certainly have been suggestive that the payload can penetrate and treat CNS disease, but nothing that I've seen yet in terms of brain metastases in HER2-low.

Dr. Matthew Goetz:

Great, thank you. Well, it's a leading question because actually, as it turns out, with this particular patient, while on paclitaxel, she actually developed symptomatic brain metastases that required whole-brain radiation. Unfortunately, she passed away 3 months after completing whole-brain radiotherapy. So I think Kevin, you really bring up an excellent point and one of the things I'm anxious to see, I suspect that the numbers will be very small and I don't think I've looked at the small print as of yet from DESTINY-04, but was there any difference in terms of the incidence or the subsequent sites of progression in brain versus not in patients who were randomized to trastuzumab deruxtecan versus dealer's choice? So that will be something that will be certainly of note because we really, for these patients with ER-positive, HER2-negative breast cancer with metastases, the brain of course, it's rare, but we really don't have a lot of good options for these patients.