This patient is 62 years old and she noted a rapidly enlarging mass in her breast. When she went to her physician, she had a 6 cm mass in her breast and she had axillary adenopathy as well. And the biopsy showed grade 3 invasive ductal breast cancer that was strongly estrogen receptor-positive, progesterone receptor-negative, and HER2 [human epidermal growth factor receptor 2]-negative. Unfortunately, on staging evaluation, she had multiple liver metastasis at the time of presentation, no other sites of metastasis. And her liver function tests were mildly elevated. Her transaminases were mildly elevated. Bilirubin and alkaline phosphatase were normal, CBC [complete blood count] normal. Otherwise, a fairly healthy woman, no serious comorbidities. So she&rsquo;s presenting with de novo metastatic disease, a grade 3 aggressive breast cancer, rapidly enlarging, already metastatic to the liver at the time of presentation.

When women present with de novo metastatic disease that&rsquo;s estrogen receptor-positive, progesterone receptor-negative, HER2-negative, and grade 3 with liver metastasis at presentation, the median overall survival would probably be in the 2 to 3 year range. It&rsquo;s quite variable, and it really does depend on the overall tempo of the disease. This woman&rsquo;s tempo, unfortunately, was a rapidly growing mass and already multiple liver metastasis at the time of presentation. Things are changing for the better with regard to our therapies. But generally speaking, the median overall survival is probably in the range of 2 to 3 years for this woman.

HR+ Breast Cancer Prognosis

This woman who&rsquo;s presenting with de novo metastatic breast cancer, age 62, with multiple liver metastasis, pretty good liver function, however, the transaminases are a little bit elevated, asymptomatic from that perspective, but a large breast mass and adenopathy, she&rsquo;s a woman that heretofore, I would have recommended chemotherapy for initially, up until pretty recently.

Historically, my standard of care would have probably been a combination of a taxane and capecitabine for 6 to 8 cycles, get maximal cytoreduction, and then proceed to capecitabine alone as a maintenance therapy for the patient, and then considering what to do with the locoregional disease, depending on whether it was likely to become a local control issue for her down the road. If it had a very nice response, I would have probably not recommended lumpectomy, radiation, or mastectomy because of her liver metastasis. But on the other hand, if it had been more of an inflammatory breast cancer, something that could create a bad local control problem down the road, I would have also been considering surgery and potentially radiation therapy for her.

So, up until recently, I would have recommended chemotherapy for the patient because of the tempo of the disease and the multiple liver metastasis. However, over the last couple of years, I have switched my practice pattern, and I would give serious consideration to utilizing a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor for this postmenopausal woman with letrozole because of the extremely good results with regard to progression-free survival with the CDK4/6 inhibitors. The median progression-free survival in the first-line setting is a bit over 2 years. And even with combination chemotherapy in the first-line setting, median progression-free survival is in the range of about 9, maybe 10 months or so. So it&rsquo;s a vast difference in terms of progression-free survival.

The other thing we think about is we need a response pretty quickly for this patient. She&rsquo;s not in extremis, but with the diffuse liver metastasis, you really do want to get control of the disease pretty quickly. The response rate with combination chemotherapy is in the order of 50%, maybe 60%. And, interestingly, that&rsquo;s about the same response rate that you&rsquo;ll get with the CDK4/6 inhibitors in the first-line setting. The clinical benefit rate in the first-line setting is about 80%. So about 80% of patients will have either a response or prolonged stable disease for 6 months or longer. So it&rsquo;s comparable in terms of the chances of getting substantial cytoreduction.

The other issue we think about in chemotherapy versus CDK4/6 inhibitors is what&rsquo;s the tempo of response because we want a more rapid response. Endocrine therapies, the response tempo tends to be slower. But with the CDK4/6 inhibitors, if you look from cycle to cycle at the degree of tumor reduction in terms of the volume of the disease or the measurements of the disease, they fall very quickly from cycle to cycle. We don&rsquo;t have head-to-head comparison data yet, although studies are planned to look at patients such as this in the first-line setting with chemotherapy versus CDK4/6 inhibitor. It looks similar to me in terms of the tempo of response. So I&rsquo;ve switched my practice patterns and would really give some serious consideration to a CDK4/6 inhibitor for this patient.

Really the only patients I&rsquo;m still utilizing chemotherapy for first-line are patients with truly visceral crisis, immediately life-threatening disease such as lymphangitic spread in the lungs with substantial dyspnea or liver function tests that are more markedly elevated where you may only have 1 therapeutic opportunity for the patients and you really have to get a response. This patient, I would definitely not put her in the category. So I think the definition of visceral crisis needing chemotherapy has become more narrow. We&rsquo;re not utilizing the chemotherapy so much in the first-line setting.

All of the CDK4/6 inhibitors have been studied with both the aromatase inhibitors, mainly letrozole but others as well, in addition to fulvestrant. And I think the hazard ratios are pretty uniformly the same across all of the studies, whether it&rsquo;s with aromatase inhibitors, whether it&rsquo;s with fulvestrant. It&rsquo;s all around 0.55 or so. So it does not appear to me that it makes a difference what the endocrine therapy partner is. Of course, the vast majority of our data are with the aromatase inhibitors and fulvestrant. There are some safety data and a little bit of efficacy data with tamoxifen. And again, it looks good. It&rsquo;s a much smaller data set. Tamoxifen/ribociclib, we want to avoid that because there could be some QTc prolongation with each of the agents. Very small percent chance, but there could be some QTc prolongation that could be overlapping, so we don&rsquo;t want to use that with ribociclib. But that is also a possibility that&rsquo;s been studied with palbociclib and abemaciclib. But I think either, usually we&rsquo;re going to use the aromatase inhibitors or fulvestrant. I don&rsquo;t think it makes any difference.

When to Choose Chemotherapy vs CDK4/6 Inhibitors

With regard to which of the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors I would consider for this particular patient with the de novo metastatic disease with the multiple liver metastasis and mildly elevated liver function tests but pretty asymptomatic, I would utilize abemaciclib because of the tempo of her disease. She has grade 3 disease with a rapidly growing mass in the breast and now multiple liver metastasis. And the reason I would utilize the abemaciclib is mainly because of subset analyses that have looked at liver metastasis, grade 3 disease, progesterone receptor-negative disease, several of the characteristics that define this woman&rsquo;s cancer have been looked at with abemaciclib. And in the first-line setting, there can be a difference of improvement at 30% response rates looking at letrozole with or without the abemaciclib, even in these concerning clinical characteristics, the more aggressive virulent type disease.

The first-line data for all of the CDK4/6 inhibitors show excellent improvement in progression-free survival with palbociclib, ribociclib, abemaciclib, really identical in terms of the overall populations. So any of them would be reasonable options truthfully. The issue is what about this particular virulent subset. Most patients with first-line metastatic breast cancer do not have this aggressive biology. So the totality of the data are going to be more reflective of patients with more indolent or moderate disease. The biology and the natural history of those with aggressive disease will not be necessarily manifest in the overall data.

You have to look at some of the subsets to really understand. The thing about abemaciclib is it&rsquo;s every day. There is no break with abemaciclib to allow for narrow recovery. And so with more virulent disease, there may be some benefit. We don&rsquo;t know because there are no head-to-head comparisons, but there may be some benefit from a continuous inhibition of CDK4/6 as opposed to the 3 weeks on, 1 week off schedule that&rsquo;s required for the palbociclib and ribociclib. So that&rsquo;s the theoretical reason, potentially a little bit broader spectrum of activity, but again, these are not based on head-to-head comparisons but more subset analysis.

But in the MONARCH 2 and MONARCH 3 clinical trials, both first-line with letrozole and then second-line with fulvestrant, when abemaciclib was added to these endocrine therapies and looking at some of the key clinical characteristics; liver metastasis, short treatment-free interval, progesterone receptor-negative, grade 3 disease, there were very large improvements in both response rates and progression-free survival with the abemaciclib. And a bit more so even than patients with more indolent features such as bone-only disease, progesterone receptor-positive, longer treatment-free interval. They too benefitted from abemaciclib, but interestingly not to the same extent that the more virulent cancer did.

Now, the other agents as well also have activity in liver metastasis and grade 3 disease, progesterone receptor-negative. But the in-depth analysis has been done most with abemaciclib in these patients with the more concerning clinical characteristics. And the fact that you don&rsquo;t have to take the week off is appealing to me. So no head-to-head comparisons, but that&rsquo;s the reason that I generally, if I&rsquo;m going to forego chemotherapy, when I&rsquo;m on that borderline does this patient need chemotherapy or could I utilize a CDK4/6 inhibitor, that&rsquo;s where I will choose abemaciclib for that particular patient. For the more indolent patients, I don&rsquo;t choose abemaciclib. I utilize palbociclib or ribociclib for the patients with bone-only disease or more ER [estrogen receptor]-driven disease because there&rsquo;s less GI [gastrointestinal] toxicity. The abemaciclib I find patients do fine with it, but I want continuous inhibition of CDK4/6 for patients with more virulent disease.

I&rsquo;ve had a chance to have a fair amount of experience with all of the CDK4/6 inhibitors. And because abemaciclib is also approved later-line for patients and has been studied later-line, I&rsquo;ve had the opportunity to see some very robust responses, including in patients with diffuse liver metastasis, even in heavily pretreated patients. That truthfully was what made me interested in abemaciclib, was seeing these patients very late-line and seeing the non-cross resistance, the real robust activity.

One patient in particular was a veterinarian, African American veterinarian. She was very heavily pretreated by the time the CDK4/6 inhibitors became available, and she had not been exposed to one. And she had basically had all of our available endocrine therapies and chemotherapies at that time. She had diffuse liver metastasis, even some hyperammonemia. She was having some liver failure. She had just finished radiation therapy for brain metastasis. Her performance status was not good, and I treated her with fulvestrant and abemaciclib, and she had a major response that lasted for about a year with an excellent quality of life. So that kind of put me back on my heels a little bit, I will say, and that&rsquo;s been of great interest to me. I have several other patients who were in that category. So, when I saw the subset analysis of those patients with the liver metastasis, the more virulent disease, shorter treatment-free intervals, etcetera, it made sense to me based on my clinical experience.

Abemaciclib With Endocrine as Frontline Therapy

One of the things we have to tell our patients when they&rsquo;re starting CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors, of course, is about the toxicities and what to expect. And this patient, I would choose letrozole and abemaciclib for her, and I would tell her that diarrhea would likely start as well as potentially some nausea, a little bit of dyspepsia. It might start within a few days and to have loperamide at the ready. Generally, I don&rsquo;t start the loperamide prophylactically because not everybody has diarrhea, but have it there. If a woman started to have several loose stools, my standard approach is to take 2 loperamide after the first loose stool of the day and then 1 after each subsequent loose stool. And then usually after 1 or 2 doses it will stop.

Now, the diarrhea on the abemaciclib is really the first 4 to 6 weeks. It tends to get much less after that, and what I have found, my patients have taught me, for a woman, they have figured out that eating lighter, not eating heavier meals and eating smaller amounts at a time, blander, will decrease the diarrhea. So women will have, after 4 to 6 weeks, they&rsquo;ll have 1 or 2 loose stools a week, and it will generally be because of some deviation in their diet. So it&rsquo;s actually quite manageable over time with the occasional loperamide and some dietary modification.

Other than that, not very much in the way of toxicity, a little bit of fatigue but not very much. In my experience, I&rsquo;ve probably only had 2 or 3 women where I needed to reduce the dose of abemaciclib because of diarrhea. Most of the women, the diarrhea has drastically decreased over the first few weeks, and they&rsquo;ve been able to stay at the 150 mg twice a day. But the dose reduction does help, down to 100 mg twice a day. It does help. There&rsquo;s more diarrhea at the higher dose of 200 mg twice a day, which is the FDA approved dose for the single agent later-line therapy.

CDK4/6 Inhibitor Toxicity Management

We are still at the early stages of learning about resistance mechanisms in the clinic to the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors, and we don&rsquo;t have any clinical data yet that give us clear guidance about which therapeutic options have efficacy after progression on CDK4/6 inhibitors. There was an interesting paper by Nick Turner [MD] and colleagues from the PALOMA-3 trial of fulvestrant and palbociclib in the second-line metastatic setting looking at ctDNA [circulating tumor DNA] before and after treatment with palbociclib. And about 5% of patients had new mutations in

, and that was probably a mechanism of resistance to the palbociclib. Interestingly, there was a bit of an increase in estrogen receptor [ER]

mutations. Again, maybe that was a bit more of a resistance mechanism to the fulvestrant, potentially. There was a little bit of an increase as well in

mutations, PI3-kinase mutations, also some HER2 [human epidermal growth factor receptor 2] mutations, so it looks like a variety of mechanisms.

Carlos Arteaga [MD] and colleagues have shown that

amplification can be a resistance mechanism to CDK4/6 inhibitors. So it&rsquo;s actually going to be a variety of mechanisms. Preclinically, the PI3-kinase pathway appears to be quite important, so that if you then block the estrogen receptor CDK4/6 and the PI3-kinase pathway, you can get some very good antitumor synergy against the cancer. So I think the PI3-kinase pathway will be a very important one resistance wise. We await the FDA approval of the first oral PI3-kinase inhibitor for breast cancer patients, alpelisib, based on the SOLAR-1 clinical trial result. That was with fulvestrant plus alpelisib showing substantial improvement in progression-free survival for patients with PIK3CA mutations. About 40% of patients with ER-positive metastatic breast cancer have a PIK3CA mutation.

What I think is going to happen once that agent is available to us is when our patients are receiving first-line CDK4/6 inhibitor therapy, we will probably send off their tissue for the analysis of the PI3-kinase. Most of these mutations are present in the primary breast cancer, so that you can utilize a primary breast cancer to do the next-generation sequencing and see the PI3-kinase mutations. Interestingly though, it also looks like ctDNA in the metastatic setting will also be useful to find PI3-kinase mutations. I think that upon progression on CDK4/6, utilizing ctDNA over time will end up being useful to us. So we wait. We don&rsquo;t have that agent available now, but over time, I think we will have alpelisib and will be able to utilize it upon progression on CDK4/6 inhibitors for those patients with a

Assuming that this patient does well with the abemaciclib and the letrozole, upon progression with multiple liver metastasis, probably my next recommendation would be single-agent capecitabine, outside of a clinical trial. There are clinical trials that I would immediately want to put her on. But outside of a clinical trial, probably capecitabine. I do utilize everolimus and exemestane for some patients, so that&rsquo;s a possibility for the patient as well. But in my experience with diffuse liver metastasis, generally I would go on to capecitabine next for the patient. Although the everolimus would be something I would consider potentially after the capecitabine. Then hopefully if her cancer has a

mutation, I would consider alpelisib down the line for her as well, but if she were not mutant on

, probably capecitabine and then consideration of the everolimus, exemestane.

Treatment Following Relapse on CDK4/6 Inhibitors

The main clinical point for this patient is that historically, pretty much all of us would have recommended chemotherapy at presentation with a rapidly enlarging breast mass, axillary adenopathy, and multiple liver metastasis. I think chemotherapy would have been the go-to therapy. We probably would not have utilized single-agent endocrine therapy because of the tempo of the disease. And I think the sea change in clinical practice is the consideration of CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors for this patient.

The data suggest that they&rsquo;re equal to chemotherapy, with CDK4/6 inhibitors plus endocrine therapy, equal to chemotherapy in response rates, clinical benefit rates, tempo of response, but much longer progression-free survival, and of course much less toxicity. So an overall win for the patients. And I think that my practice pattern has slowly evolved over the last couple of years, and I would be comfortable with abemaciclib for this patient because of the subset analysis, specifically in the subsets of patients with her concerning clinical characteristicsprogesterone receptor-negative, liver metastasis, grade 3 disease. So that would be my choice for this patient. And hopefully we&rsquo;ll see some head-to-head comparisons over time specifically for this patient.

A Case of HR+ Metastatic Breast Cancer

HR+ Breast Cancer Prognosis

When to Choose Chemotherapy vs CDK4/6 Inhibitors

Abemaciclib With Endocrine as Frontline Therapy

CDK4/6 Inhibitor Toxicity Management

Treatment Following Relapse on CDK4/6 Inhibitors

HR+ Metastatic Breast Cancer Treatment Sea Change