 I want to reinvent this case for Nick. Let’s say that this same patient who progressed in her fourth year of adjuvant AI [aromatase inhibitor] and got 2½ years of benefit from fulvestrant and ribociclib had a wild type 

 in lung and bone at the time of progression, so she’s not mutated. Nick, take us through your algorithm in terms of how you’re thinking about therapy. Let’s say she’s not in visceral crisis and she’s had 2½ years on fulvestrant CDK4/6 inhibitor. What’s on the menu?

 In a case like this, the factors that make me decide which way I want to take this patient in terms of the next lines of therapy are the specifics of the case, what the actual disease progression is looking like, and whether the patient’s performance status is significantly hindered. As you mentioned, she’s not in visceral crisis, so that’s reassuring at least.

There are number of different questions. We have different degrees of answered and unanswered questions. One of the most common questions that comes up in my clinic from my patients is, “Can I return to a CDK4/6 inhibitor? Should we switch the CDK4/6 inhibitor?” We have limited data, and we’re awaiting results from the randomized maintained trial looking at patients who had progressed on palbociclib or ribociclib plus an aromatase inhibitor. Those patients are being randomized to either fulvestrant or fulvestrant plus ribociclib. That will be a very helpful study in helping us understand if there’s a role for just switching the endocrine therapy partner but continuing some form of a CDK4/6 inhibitor as an immediate next line of therapy.

We don’t have any prospective data in this, but there was a retrospective analysis of 4 different centers performed by Seth Wander et al and presented at 2019 ASCO [American Society of Clinical Oncology] Annual Meeting. There were about 58 patients in this retrospective analysis who had received either a single agent or combination of abemaciclib and had progressed on that. They had then received either 1 non-CDK4/6 inhibitor-containing therapy in between resuming CDK4/6 or had gone on to another CDK4/6. About one-third of patients had early progressive disease. However, one-third of patients did have a significant clinical benefit in greater than 6 months. Then about 17 of the patients had been continuing on the CDK4/6 inhibitor at the time of analysis. There seems to be, at least in some retrospective data, some benefit of continuing or switching a CDK4/6 inhibitor. But until we have some randomized data helping us understand the true benefit of this, I tend to prefer other regimens, especially a regimen that would contain an mTOR inhibitor, such as an everolimus.

That would then bring us to some of the studies that have shown benefit with the use of everolimus plus exemestane. Certainly, the BOLERO-2 trial showed patients who had progressed on a nonsteroidal aromatase inhibitor. There was improved median progression-free survival with the combination of exemestane plus everolimus, which is what helped this combination gain approval by the FDA.

Of course, there have been other retrospective studies that are more modern, including the EVERMET trial. EVERMET was a retrospective study that looked at patients with both prior CDK inhibition and without CDK inhibition, and then also in the first-line setting who had received the combination of everolimus and exemestane. It showed that median progression-free survival was worse in patients who had received a prior CDK4/6 inhibitor, which isn’t surprising. But I don’t think this would steer me away from recommending this regimen in such a case. My general practice is to extinguish all targeted therapy options prior to moving on to chemotherapy.

 I’m going to go off-script for a second and ask you each to give me a 15-second answer. Do any of you find a place for tamoxifen in such a patient as a consideration for third-line endocrine therapy? Dejan, why don’t you start?

 Not in the second line. The treatment paradigm for me is very simple in the second-line setting for CDK. I use fulvestrant-alpelisib for patients with 

 mutations regardless of prior use of fulvestrant. Wenow have 2 data sets that show that prior fulvestrant doesn’t really matter. For patients who are a wild type, I use fulvestrant-everolimus based on PrECOG data, regardless of whether they had prior fulvestrant. I will use tamoxifen. Interestingly, tamoxifen has activity against some 

 mutants. I’d consider it in the third-line setting in patients who are really doing well, have low disease burden, and are progressing under second-line therapy but could benefit from some additional hormonal blockade and are not candidates for clinical trials for whatever reason.

 Hope, in half that amount of time—15 seconds—is there a place for tamoxifen in the third-line endocrine setting for any of your patients?

 Yes, I think so. We have data with tamoxifen and everolimus. If a patient has received fulvestrant without a partner and doesn’t have a 

 mutation, I could see giving tamoxifen; especially in patients with the 

 mutations with everolimus, based on the first data we saw. I have a patient who missed the CDK4/6 inhibitors, and she responded to tamoxifen and CDK4/6 inhibitor with PCR [polymerase chain reaction] in liver for 2 years. It definitely still works in the endocrine-sensitive population.

 Nick, you’ve heard of tamoxifen. I know you’re a young oncologist. Have you used it in the third-line metastatic setting, or is it just not sexy enough?

 I feel bad for tamoxifen. It gets forgotten about in the age of glitzy combination regimens of targeted molecular therapy and other more recent endocrine therapy partners. But yes, I would certainly consider going back to tamoxifen or trying tamoxifen, especially in patients who have demonstrated at least in the first-line setting significant endocrine therapy sensitivity. But I agree that I’d extinguish all other combinations of molecular therapy partners and clinical trial options, including single-agent endocrine therapy trials that are looking at some of these newer agents, including oral SERDs [selective estrogen receptor degraders] and some of the PROTAC [proteolysis-targeting chimera] inhibitors. There’s certainly need for more endocrine therapy partner choices, and we should be trying to enroll patients in trials to help us understand the benefit of that. I would go back to tamoxifen, which I certainly have heard of.

Videos

Breast cancer experts comment on whether there is a benefit to switching to or continuing on CDK4/6 inhibitors with disease progression for HR+ metastatic breast cancer and discuss the use of tamoxifen for third-line endocrine therapy.

Using CDK4/6 Inhibitors After HR+ mBC Disease Progression

 To put a human face on this, I’d like to present the case of a 56-year-old postmenopausal woman who was diagnosed with stage IIB, hormone receptor–positive, 

 [human epidermal growth factor receptor 2]–negative breast cancer on core biopsy. She originally underwent breast-conserving surgery. We were told that she had node-negative disease and a recurrence score of 28. She received adjuvant docetaxel and cyclophosphamide, had adjuvant radiotherapy, and was placed on an adjuvant aromatase inhibitor [AI]. Four years into her adjuvant aromatase inhibitor, she presents with coughing and some dyspnea. Unfortunately, imaging shows metastatic recurrence involving lung as well as bone in her thoracic spine and ribs. This is confirmed by lung biopsy as an ER [estrogen receptor]–positive, 

- breast cancer, similar to her primary tumor.

This occurred while on adjuvant AI. Then she received fulvestrant plus ribociclib as her first therapy for metastatic disease. She also had stereotactic radiotherapy to the spine. She did well with this for almost 2½ years, but now she’s progressed further in the same organ systems in lung and bones. Her ECOG Performance Status is 1, her laboratory abnormalities are normal, and the therascreen PCR [polymerase chain reaction] assay was sent for 

 mutation and revealed the E545K hot spot mutation. Would anyone like to begin the discussion on this 1? Hope, do you want to tell us how you would think about this patient who enjoyed 2½ years of progression-free survival [PFS] on first-line fulvestrant plus ribociclib but has now progressed and has a hot spot 

 These are such tough situations when a patient relapses on their adjuvant endocrine therapy. I wish we had a better idea of how to recognize these patients up front and intervene earlier. Maybe some of the data we’ll talk about a little later will give us that path. In a patient like this, you’ve already used your SERD [selective estrogen receptor degrader]. You’ve given fulvestrant, so you can’t use SOLAR-1 as your primary direction. I usually don’t like to continue the same endocrine agent when a patient has developed progressive disease and has visceral metastases, although I’m sure we could all find exceptions to that.

In this situation, I would use the data from the BYLieve study, which is a nonrandomized phase 2/3 cohort trial. Cohort B, which was presented at 2020 San Antonio Breast Cancer Symposium, looked at the patient population who had progressed most in their last therapy on fulvestrant and a CDK4/6 inhibitor. They received the AI letrozole with alpelisib if they had a 

What was important was that we looked back to see how many of those patients had received a nonsteroidal AI or any AI within a 6-month period of time of developing metastatic or progressive disease, and it was a very high number: in the 80% range. In those patients, we did meet our end point. It looks like the benefit in these patients who are more heavily pretreated might be a little less. But these are single-arm phase 2 trials compared with SOLAR-1, where patients had relatively less treatment. I’d use that data as a way to direct her treatment, and I’d give a nonsteroidal AI with alpelisib as her next treatment.

 Thank you for that. It’s great to have data. The median PFS in that cohort B was in the range of about 6 months, which was better than expected.

 Yes, it was. We’ve had some discussions about that. Could it be alpelisib alone? We certainly see activity alone, but there may be some synergy that we’re not able to identify in a single-arm trial in which you give an AI that we wouldn’t normally give after a patient progresses. You add a targeted agent, and we’ve all seen that anecdotally where patients did much better than we would have expected when we take an approach like that.

 There’s also been some recent real-world data to help us understand the clinical trial data. Do you find that data to be helpful at all?

 Yes. It’s helpful more from a safety tolerability perspective. I would always exert caution in interpreting the PFS. In these studies, it’s not the same trigger. You don’t have scans at the same frequency, so just looking at the PFS could be problematic. But from a safety tolerability, the discontinuation is very helpful.

Coming back to what was discussed earlier about real-world studies at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting, we had the experience from the French group, which looked at their expanded access program. Their experience was that the combination was well tolerated and had efficacy. They did some multivariate analysis to see if there are certain predictors in terms of who would really do well with fulvestrant plus alpelisib. They found that prior use of everolimus was not a predictive factor in terms of doing worse or better with alpelisib. Surprisingly, prior use of fulvestrant was associated with improved outcomes with fulvestrant plus alpelisib.

Taking the caveats of a real-world study, you could consider fulvestrant plus alpelisib for this patient. Although I agree with Hope that, in general, we like to switch the endocrine partner. When someone has progression on letrozole plus CDK4/6, we’d like to do fulvestrant plus something else. It’s just the opposite here. With a patient who had progression on fulvestrant plus ribociclib, I’d like to do an AI plus alpelisib. I’d also like to get plasma-based genotyping in this setting. We saw that there was a 

 mutation, but it’s important to ensure that there’s no 

 mutation, I would not use an AI and would continue fulvestrant.

 mutation. There are more of those differences in the more resistant 

 mutations, as Dejan was talking about earlier. We didn’t look at this in the population of patients. We know there was a percentage of patients in BYLieve who had 

 mutations. That’s what we see. We see them acquired with fulvestrant as well as AI. I wouldn’t use that as a differentiating factor until we know for sure that’s not a benefit. We also had a poster at ASCO this year with Foundation Medicine in which we looked at all the mutations that were not SOLAR-1 mutations. SOLAR-1 used the specific, more frequent mutations—I asked them, “How did you select these?” Dejan can comment on that, but there was actually no answer. It was just about choosing the more frequent ones. The interesting thing is that in the real-world setting, we seem to see benefit across this whole spectrum of the 

 mutations isn’t absolute but rather relative. There’s some wiggle room.

Andrew D. Seidman, MD, presents a case study of a 56-year-old postmenopausal woman diagnosed with stage IIB HR+ breast cancer and leads the discussion on approaching treatment for the given patient.

Case Discussion: Resistance to CDK4/6 Inhibitors in HR+ mBC

 I want to come back to where we started in terms of genomic profiling. Dejan, I’ll let you take the lead on discussing how common 

 mutations are, which mutations were primarily seen in SOLAR-1, and what the prognostic implications of these mutations are. What have we learned since SOLAR-1?

 is a gene that encodes PI3 kinase alpha. It’s a really important regulator of cell signaling, mediating growth signals that come from the membrane of the cell and go into the cell cycle machinery. The activating mutations in that gene and resulting activation of the protein itself are present in 40% of patients with ER [estrogen receptor]–positive metastatic breast cancer. This is the most common actionable operation we have. The only 1 that even matches their prevalence would be 

, which is not as actionable. There are some clinical trials in that space, but at the moment, it’s not something that’s clinically actionable. As Aditya explained, we certainly should pay attention to 

 from the beginning, or the first diagnostic specimen.

The mutations in PI3 kinase happen in 2 different areas. First are called hot spot mutations, which are present in these 2 domains of the proteins: helical and kinase. The vast majority of patients have 1 of those mutations, either in the helical or the kinase domain. A few patients will have both. It’s those 2 areas of the protein or gene that really matter.

In the SOLAR-1 trial, we focused on 11 mutations in total. They mostly spanned these hot spot mutations. We had another area called exon 7 that we looked at, but that was it. It was 11 mutations in exon 7, 9, and 20 of the gene. This is about 80% of all 

 mutations, but it’s not all of them. We should first look at the data we have from SOLAR-1 on these hot spot mutations. The benefit of alpelisib added to fulvestrant compared with placebo plus fulvestrant is undeniable.

We should also run an additional analysis to look at what we call non–hot spot mutations. These mutations are outside these commonly mutated areas, which can also activate the protein. This is where it becomes a little challenging for a clinician. It goes back to comments made earlier by Hope and Aditya. It’s not just presence of mutation. It’s also the type of mutation that matters. For hot spot mutation, we’re on a safe ground, but with non–hot spot mutation, we have to work with our micropathologist and try to understand if this is mutation that we see. I’ll give you one example: R88Q, which was not in the initial 11 mutations of SOLAR-1. But is that mutation altering the function of the protein? Is it likely to activate the pathway? If it is, I would argue that this is the setting where we should be studying or using PI3 kinase alpha inhibitors like alpelisib. Where the difficulty continues is when you start comparing the tissue vs blood.

 Yes. Let me ask Aditya. Do you start with looking for plasma circulating tumor DNA and resort to tissue first, or is it more of a practical decision? Maybe your patient just had a recent biopsy and you’ve got the tissue, so you won’t order the plasma. What’s your algorithm at MGH [Massachusetts General Hospital] for approaching 

 If someone has a tissue biopsy, we’ll consider genotyping from the tissue biopsy, particularly in the first-line setting. After that, it’s usually plasma-based genotyping. One additional advantage of plasma-based genotyping is that if the initial tissue-based genotyping then shows a PI3 kinase mutation and the patient has progression on letrozole plus CDK4/6 inhibitor, a subset could have acquired 

 mutations that you can detect in the blood. To give the patient the maximum chance of getting access to a PI3 kinase inhibitor, that’s a really good time to get plasma-based genotyping.

 We recently saw that Fabrice André published the updated overall survival from SOLAR-1 in 

. There was an 8-month advantage for alpelisib vs placebo when combined with fulvestrant, which didn’t achieve statistical significance with a hazard ratio of 0.86. Yet for an interesting subset of patients with visceral disease, the curves seem to be more separate. Does anybody want to offer some thoughts on that result?

 It’s an interesting thing. I certainly don’t claim to be an expert on statistical design, but we have to distribute alpha, and the overall survival differences that are made as secondary end points are sometimes way outside what anyone would consider to be feasible in this. Although with CDK4/6 inhibitors, we saw even greater differences from what we would have guessed.

In this population, the numerical difference was interesting, but it really has to do with the calculated curves over time. The medians were not different in terms of the statistical calculations that were needed for the study. But when we looked at the visceral group of patients that we would have expected to do much more poorly, we saw a suggestion of a benefit. Even though you can’t make a statistical conclusion about that, it’s very encouraging for us in treating patients in this setting where you want to avoid going to chemotherapy. You know there’s a 

 mutation, and you can treat a patient who has relatively more endocrine-resistant disease by phenotype or by clinical presentation. I thought those were helpful data clinically.

 Yes. I believe the number was 37 vs 23 months in the patients with visceral disease who had 

 mutations. It’s a whopping difference numerically, but it’s a small study. The entire cohort for patients with 

 mutations was only 341 patients, so we had to answer many questions.

What’s clear, though, Andrew, is that it looks like patients with visceral disease and 

 mutation do quite poorly. We need to either deploy drugs like alpelisib there in the clinical setting or seek clinical trials for them, because they generally don’t do well. That matches some of the other analysis of CDK4/6 clinical trials, both MONARCH 2 and MONALEESA-3 trials. The abemaciclib and the ribociclib studies in ER-positive disease have shown that patients with 

 mutations tend to perform less well on both the experimental arm on the CDK4/6 arm and the control arm.

 Although you benefit those patients with CDK4/6.

 doesn’t appear to be a predictor for CDK4/6 benefit, but if you look at absolute numbers, they tend to perform less well compared with wild types in both arms.

Dejan Juric, MD, leads the discussion on the role of PIK3CA mutations in HR+ metastatic breast cancer.

Implications of PIK3CA Mutations in HR+ mBC

Nick and Aditya, I wonder if you could weigh in on this. Once upon a time, we used to have Coke vs Pepsi trials, the paclitaxane story, the paclitaxel and docetaxel story, and the war of the aromatase inhibitors. In an era when we may lack comparative data between palbociclib, ribociclib, and abemaciclib, how do you parse this embarrassment of riches in terms of the differences in eligibility criteria or patient characteristics? Can you walk us through that? I’ll let Nick start.

 It’s a really good point. Hope brought up a great point as well in terms of the differences in eligibility criteria with these studies. While the data with palbociclib, in terms of prespecified overall survival end points, did not meet its overall survival end point, the subsequent analysis, exploratory analysis, as well as other interesting overall survival analyses looking at real-world evidence in the Flatiron database suggest that there is potentially overall survival benefit with palbociclib. It makes you more inclined to question whether these differences in survival that we’re seeing are primarily because of study design and inclusion of patients who weren’t included in the other trials.

I tend to focus on the fact that these drugs work in very similar ways. We know that they are different compounds—certainly because they have different adverse-effect profiles, and preclinical studies showed that they have differential impacts on CDK4 vs CDK6. But I completely agree that all the predictive biomarker studies haven’t identified a single patient who especially benefits or doesn’t benefit from the combination of these drugs. Given that we’re seeing that overall survival in the first-line setting does seem to be improved, we should be using this combination at first rather than in a sequential manner and waiting until later progression. As Dejan mentioned, that later progression may make you miss that window to give them a highly effective drug.

Yes. Dejan and Aditya, maybe you can weigh in on how differential toxicity, if you see any, may be a factor in patient selection for a specific CDK4/6 inhibitor.

 Absolutely. Going back to what you were saying earlier about Coke and Pepsi: Both are carbonated drinks, but people have preference of 1 or the other. There are other factors to consider, such as access and finances. It’s a similar issue with CDK4/6 inhibitors. Ribociclib, palbociclib, and abemaciclib are all good agents. The decision to choose 1 over the other essentially boils down to patient preference in terms of the adverse effects, ease of access in terms of co-pays, and dose reduction.

If you talk about the toxicity profile, ribociclib and palbociclib tend to cause more myelosuppression, while abemaciclib tends to cause more diarrhea. From a dose-reduction perspective with palbociclib, you have to change pills from 125 to 100 mg if someone needs dose reduction. It’s another call to the insurance company and getting the new supply of 100 pills. With ribociclib, you start with 3 pills, and if someone has adverse effects, you can go down to 2 pills. There’s a convenience factor that’s built in. Finally, it’s physician experience. Because palbociclib was approved first, physicians in general, particularly in the community, have more experience with palbociclib. It’s all these factors that come into the decision-making: adverse effects, ease of access, patient and provider preference.

 Could I ask a quick question for everybody? There have been some comments, even at the ASCO [American Society of Clinical Oncology] discussion, about differences in the blockade of CDK4 vs CDK6 and things like that. I totally agree with what Aditya said about the access. Another thing to consider, which I recently ran into, was Medicare patients having to pay their share of cost on each drug. If you got a 150 mg and a 100 mg, you’d have to pay twice as opposed to once, which is ridiculous of our health care system. I’m really interested in what everybody thinks about this difference in CDK4 inhibition and whether that plays a role in your decisions to use 1 drug vs another.

 Speaking of boxing, this could be a boxing match. My view is that these drugs are actually different. They have different chemical structures. They have different target inhibition profiles. They have different adverse effects. While some outcomes are the same, some outcomes aren’t. We’re going to discuss early stage disease later, but this is where a can of worms is open: when you start comparing drugs and metastatic vs early stage disease.

Top-line data from all these studies show, at least when you look at the ratio for progression-free survival, that they seem to be the same. But that’s not the only outcome we care about. We care about other outcomes, such as overall survival, long-term responders, and toxicities. My view is that instead of extrapolating, we simply use the data we have in that patient population. If I have a premenopausal patient, I’m prescribing ribociclib. If I’m interested in a patient who has primary endocrine-resistant breast cancer, a high visceral disease burden where ER [estrogen receptor] and PR [progesterone receptor] status are questioned in terms of their amount or positivity, and I’m not worried about GI [gastrointestinal] toxicity, then I really like abemaciclib.

We have to pay attention to where the primary data were generated. When we have the data in that patient population, my preference is to use the drug from that particular trial and setting. The discussion about class vs specific drug is really important for PI3 kinase inhibitors. We have gone through 4 generations of PI3 kinase inhibitors. We call them all PI3 kinase inhibitors, but only 1 of them has been approved so far because it had a PI3 kinase alpha inhibition as the dominant target. Hope, to go back to your question about whether CDK4 vs CDK6 matters, I think so. Breast cancers tend to be really dependent primarily on CDK4, at least initially, and palbociclib is equipotent there, while the other 2 drugs preferentially hit CDK4. That may not necessarily come into play initially in the first readouts of these trials, but they may play a role as you start looking at a longer effect or more distant clinical end points.

These are great points. They may have different implications in the early stage setting and in the metastatic setting, and we’ll absolutely come back to that.

Experts in breast cancer comment on the appropriate patient selection of CDK4/6 inhibitors for the management of HR-positive metastatic breast cancer. 

Selecting a CDK4/6 Inhibitor for HR+ mBC

Hope, could you provide us a high-level overview of what the landscape looks like in first-line endocrine therapy with CDK4/6 inhibitor use? We’ve got evolving data and some new updates in terms of overall survival. Do you want to take us through some of those studies?

 It’s a very interesting area because we’ve seen a lot of survival data in the second-line-or-greater setting. For example, for abemaciclib in MONARCH 2, we’ve seen a survival difference that was significant with the addition of abemaciclib to fulvestrant. Most recently at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting, we saw an additional update from PALOMA-3, which is a unique trial in that it included patients who had received about a third of prior chemotherapy and multiple lines of treatment where the control arm didn’t do as well, suggesting that the group who didn’t get chemotherapy, who presumably are more sensitive to endocrine therapy overall, had a survival difference in line with the other trials. We have data with ribociclib as well. In this setting, the data showed us a survival benefit in patients who have a shorter median PFS [progression-free survival] overall, because they’re pretreated with endocrine therapy or chemotherapy.

Most recently, first at the 2020 San Antonio Breast Cancer Symposium, we saw an update of the MONALEESA-7 trial with overall survival. This had already been published in the 

, and I was fortunate enough to write the editorial on that. For the first time, it showed a survival difference in a first-line setting in a pre- and perimenopausal group of patients who clearly have more highly proliferative disease that’s less endocrine sensitive. In that group of patients, there was a significant survival benefit at the final analysis in 2019, but the median overall survival in the ribociclib group had not been reached. Patients could receive the nonsteroidal AI [aromatase inhibitor] or tamoxifen. The recommendation has been not to partner with tamoxifen due to a small increase in QTc prolongation, which isn’t seen to that degree with aromatase inhibitors.

Debu Tripathy presented these updated data, which was an ongoing analysis of overall survival. It was quite remarkable. The median overall survival was increased by almost 11 months with a hazard ratio of 0.76. This group of patients has worse disease. If you looked at who received the nonsteroidal AI, the difference was 11 months, which is the same. This was almost 700 patients, and it was practice changing.

At ASCO we saw an update of the MONALEESA-3 trial, which was a unique study in that it included patients in the first- and second-line settings. There were early relapsers in the second-line setting as well. It’s a large study, with over 700 patients, and they all received fulvestrant as a backbone. That’s also quite interesting. They’ve showed that in the second-line setting, the absolute difference in overall survival is highly significant, and there’s a 6-month difference. They still haven’t reached the median in the first-line setting, but the hazard ratio is 0.64, showing a benefit in the first-line setting in this group of patients who were postmenopausal 1 way or another. The other exciting data that were shown was a hallmark analysis at 5 years showing that at 5 years, 31% of the patients who were receiving placebo and fulvestrant were alive vs 46% receiving ribociclib. That’s quite interesting.

There are a lot of other analyses that have been done looking at time to first chemotherapy, chemotherapy-free survival, and progression-free survival; all of which are dramatically longer in the group that received ribociclib. We have differences in endocrine partners. We know that nonsteroidal aromatase inhibitors are very effective. In this pre- and perimenopausal group, there’s a survival difference. Thankfully for our patients, we’re still waiting for the postmenopausal women to get the number of events.

For fulvestrant, we’re seeing a benefit with survival. These are really important. We’ve seen a lot of benefits in the first-line setting in terms of PFS but not yet survival, except for in these high-risk groups. We’ve talked about the disease-related factors, what to do, and who should receive front-line CDK4/6 inhibitors, but it’s hard to find a patient who shouldn’t get a CDK4/6 inhibitor in the first-line setting based on all these accumulated data.

I was going to ask that question. I don’t know if anyone else wants to chime in on this. Is there a patient who, in the first-line setting, you should be shying away from giving a CDK4/6 inhibitor? Does anyone want to take that?

 It’s hard to find that patient. The impact of CDK4/6 inhibitors in the treatment of an ER [estrogen receptor]–positive metastatic breast cancer patient cannot be overstated. As a fellow, we would quote overall survival in patients with metastatic breast cancer as approximately 2 years. In many of these studies, we’re now seeing 4 or 5 years. I often say I’m a simple man. You want to use the best-possible therapy when the patient is in front of you with preserved organ function, with good quality of life, and we need to hit the cancer hard where it hurts—ER and CDK4/6—and not allow for the disease burden to increase, the number of cells increase, or the number of resistance mechanisms increase. Later use of these therapies can be problematic. Some patients may never get that treatment if something catastrophic happens in the first-line setting. In my mind, it’s challenging to find a patient in whom you don’t want to use a CDK4/6 inhibitor.

To use a boxing analogy, you’re looking for a knockout, not a win by decision.

A review of data from key phase 3 clinical trials, including ASCO 2021 updates, assessing the use of CDK4/6 inhibitors with endocrine therapy for the frontline treatment of HR-positive metastatic breast cancer. 

Using CDK4/6 Inhibitors in First-Line Treatment of HR+ mBC

Ruth O’Regan, MD; Joyce A. O’Shaughnessy, MD; Hope S. Rugo, MD, FASCO; and Debu Tripathy, MD, provide insight regarding recent updates from key clinical trials on the management of metastatic 

Data from the following clinical trials are discussed:

Latest findings from the phase 2 SUMMIT basket trial on neratinib plus trastuzumab plus fulvestrant for HR-positive MBC with activating 

 mutations (Jhaveri K, et al. 2020 SABCS. Poster PD1-05).

-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial (Saura C, et al. 2020 SABCS. Poster PD13-09).

Neratinib + capecitabine sustains health-related quality of life (HRQoL) while improving progression-free survival (PFS) in patients with 

+ metastatic breast cancer and ≥2 prior HER2-directed regimens (Moy B, et al. 2020 SABCS. Poster PS9-02).

Final analysis of PERTAIN: A randomized, 2-arm, open-label, multicenter phase 2 trial assessing the efficacy and safety of first-line pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in patients with 

-positive and hormone receptor–positive metastatic or locally advanced breast cancer (Arpino G, et al. 2020 SABCS. Poster PD3-02).

A randomized, open-label, phase 3 trial of pertuzumab re-treatment in 

-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study (Yamamoto Y, et al. 2020 SABCS. Poster PD3-11).

Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in 

-positive metastatic breast cancer (Modi S, et al. 2020 SABCS. Poster PD3-06).

Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study (Hamilton E, et al. 2020 SABCS. Poster PD3-07).

Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or 

-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status (Hamilton E, et al. 2020 SABCS. Poster PD3-08).

Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases (Wardley A, et al. 2020 SABCS. Poster PD13-04).

Updated Data for Metastatic HER2+ Breast Cancer

A review of data presented at the 2020 San Antonio Breast Cancer Symposium (SABCS) examining the development and validation of prognostic tools for early stage 

First results from a phase 3 randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1–3 positive nodes, hormone receptor–positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPONDER) (Kalinsky K, et al. 2020 SABCS. Poster GS3-00).

Primary outcome results from the WSG-ADAPT HR+/HER2- trial: Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0–3 lymph nodes), Recurrence Score <26 and Ki67 response after preoperative endocrine therapy (Harbeck N., et al. 2020 SABCS. Poster GS4-04).

Continued efficacy of neratinib in patients with 

-positive early stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial (Holmes FA, et al. 2020 SABCS. Poster PD3-03).

Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in 

-positive early stage breast cancer (Ruiz-Borrego M, et al. 2020 SABCS. Poster PS13-20).

The DAPHNe trial: A feasibility study of chemotherapy de-escalation based on response to neoadjuvant paclitaxel-HP (THP) in 

-positive breast cancer (Waks AG, et al. 2020 SABCS. Poster PD3-05).

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in 

-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial (Lambertini M, et al. 2020 SABCS. Poster PD3-04).

Prognostic Tools for Early-Stage HER2+ Breast Cancer 

Breast cancer experts discuss the evolution of HER2-targeted treatments, including margetuximab, trastuzumab, tucatinib, and neratinib, along with unmet needs in patients with 

Current Treatment Landscape for HER2+ Breast Cancer

 I just want to go around. If anybody wants to make a final statement about anything you found from ASCO [American Society of Clinical Oncology Annual Meeting] that was particularly compelling or practice changing.

I guess I can start. I’ll mention the big KEYNOTE-355. Hopefully that will become a standard of care for us. We can now use gemcitabine and carboplatin-pembrolizumab once it’s available to us. We’ll await the survival data because that is really important with the atezolizumab and the nab-paclitaxel. We do want to see survival from KEYNOTE-355. I will mention that, and I will let others mention other studies that were compelling to you. How about you, Tiffany?

 I similarly think that KEYNOTE-355 is a great opportunity for us to have other chemotherapy partners together with another checkpoint inhibitor. I’m really excited to see consistent data from the PARP inhibitors beyond the germline mutation carriers. Some of it could be very quickly actionable. If you think about doing…panels on tumor that pick up a breast cancer mutation, and we’re uncertain if it’s somatic or germline, it may allow for use of elaborate in that setting.

 KEYNOTE-355 just keeps resonating, partly because of that resounding message of immunotherapy in a host of other solid tumors. So many of my partners have long been raving about the role of immunotherapy in various solid tumors. Where we’ve really struggled in the breast cancer arena of wanting to embrace it. I don’t think there is a patient that hasn’t heard of it and comes in. It was always a message of, “There is a signal but not a clear signal.”

We embrace the IMpassion data and now the KEYNOTE-355. There that clear evidence of that role, and we hope that role expands to other breast cancer subtypes as well. I like that. I’ve done some of those talks. Hope, as you know, sequential single agents and combination chemotherapy were the hot items. The pendulum shifted back to sequential single agents. When I look at chemotherapy or endocrine therapy, that was the mainstay for triple-negative and sequential single-agent chemotherapy and sequential single-agent hormonal monotherapy.

Now we’re back at embracing what I think is a platform of excellent science and unraveling some of these key pathways to going back and embracing combination therapies. They’re combinations now, not with combination endocrine therapy but combination endocrine therapy with a biologic partner, based on a very well-worked-out platform of mitigating resistance in many circumstances.

The same with triple negative is looking at chemotherapy in a combination with immunotherapy and bringing in the immune systems to really increase the efficacy of those backbone agents, which results in improvements in patient care and outcomes. I think that message from multiple presentations at ASCO this year in the endocrine therapy triple negative arena existed.

 It’s hard to add onto all the great comments that were made. Clearly KEYNOTE-355 is very helpful for us. Looking at different subsets with endocrine therapy and CDK4/6 inhibitors are helpful. We really need to understand who benefits, who doesn’t benefit, and who needs more therapy. As Denise was mentioning, we’re looking at additional combinations. We don’t want to treat everybody. The cost of therapy will be just continually expanding—not just financial costs but toxicity as well.

At ACR [American College of Rheumatology Convergence 2020], we presented data with abemaciclib, pembrolizumab, and aromatase inhibitor therapy. In that trial—which was a small trial, under 30 patients—we saw pulmonary toxicity. We didn’t really know if it was actually the triplet drugs or whether it was the fact that patients had very bad disease. Regardless, we also saw worsening of liver enzymes as well. It’s an interesting thing. As we start adding on drugs, I think we have to be careful.

 [human epidermal growth factor receptor 2]–positive group. There are a ton of trials adding immunotherapy. This is a group of patients who do really well. We saw the adjuvant 

 study at ASCO this year, where they gave the overall survival at 3 years was something like 96%, and PFS [progression-free survival] was in the 90s. It was just unbelievable. We don’t want to be throwing it at on everybody. Our task of moving forward is to understand who benefits or not.

My big interest is that if immunotherapy works for a subset of patients in the metastatic setting, we’ve got to move this faster into earlier-stage disease and understand who benefits. We need to be experts on managing and understanding toxicity, time courses, and identifying toxicity.

Lastly, at ASCO this year, we didn’t talk about the long-awaited data of randomizing patients with de novo metastatic disease to surgery, intensive locoregional therapy surgery and radiation vs not. Fascinating data suggest that if you take a long time off in patients with triple-negative disease to do local therapy, it’s worse for them than if you continue therapy. I think those are really important data for us moving forward. Those are probably the most important data for me out of that SWOG trial that was presented and was nicely discussed in the plenary session.

I do think it’s still hard to know what to do with 

-positive patients who may have long-term disease control, the de novo metastatic patients. They may benefit from surgery, and certainly patients who have a lot of local disease may benefit from surgery in terms of quality of life. But we need not be telling patients we can cure them for metastatic disease by doing local surgery and radiation.

 Yeah, that’s good. Thanks for bringing that up, Hope. That was a superimportant plenary discussion at ASCO, and it is very useful. I want to thank you again for really a rich and deep discussion of some really key data sets. It’s always fun talking with you guys and having a chance to vet the new data. Thank you very much to our listeners here today. We hope as a group that you have found this informative and useful for your practice. Thank you very much.

Notable ASCO Trial Updates

 For adding targeted agents, it appears that for the 

, PI3 kinase mutation inhibitors, like alpelisib and the other agents that were treated before, the toxicity can be a major issue. Understanding the time course helps us a lot in managing it. What’s interesting is that both hyperglycemia and rash for alpelisib peak in the first 2 weeks after administration, whereas diarrhea can be a long-term toxicity. Knowing this helps us a lot in terms of prevention.

We just published this data in from the SOLAR-1 data set. What we would have recommended is that patients have a hemoglobin A1C [glycated hemoglobin] at the end of fasting glucose before they start alpelisib. It’s really important to understand what their risk factor is. We know that patients have certain risk factors and we’re going to see more about that in further analyses of SOLAR-1.

One known risk factor is a hemoglobin A1C that is not within the normal range, which means that a patient will experience hyperglycemia during their course of treatment with alpelisib, so you need to check the glucose at day 8 and day 15. Every week for the first 2 weeks is really important.

Just telling somebody to eat low carbohydrates is really hard for patients, and you need a really low-carbohydrate diet. Another thing that people have done is to use prophylactic glucose. I think the newer agents may be better. You know, the ones that are advertised on the television all the time, but they’re SGLT2 inhibitors and are hard to get.

I am hopeful that we’ll be able to design an intervention for patients that’s prophylactic and helps in managing the hyperglycemia. They definitely need diet counseling as well. You already mentioned that prophylaxis for rash with a nonsedating antihistamine works incredibly well. They’re both issues, and you want to advise people of the risk of diarrhea and different diets, making sure they have antidiarrheal therapy around.

 Thanks, Hope. That’s fabulous. I want to hear from Denise and Tiffany. Are there any particular management strategies—things you’ve observed or your experiences?

 One of major things we learned early on with everolimus, adding the mTOR inhibitor, is that when we are combining a partner with endocrine therapy, it really is much different from the days of endocrine therapy monotherapy, in which a prescription was rendered and the patient was given a prolonged follow-up. We didn’t need lab evaluation for an aromatase inhibitor or tamoxifen or fulvestrant. A lot of those patients weren’t coming back intermittently for labs or checkups or phone calls from the nurses or even return appointments that were on a short scale.

What we’ve learned and what our practices are continuing to do is a lot of patient education. We do want to hear about things that patients are experiencing when they leave our clinic, and this may be very different from their adjutant experience with endocrine therapy with these new partners. I know from my practice, when I’m talking to a patient and they’re relieved that it’s not a chemotherapy recommendation that I’m giving for hormone receptor–positive patients.

I very quickly tell them that you can have a lot of different toxicities, so it is not the stereotype that many of the patients either from adjutant therapy have experience in terms of chemotherapy. These endocrine partners, these biologic targeted agents—hitting these key pivotal pathways—have a whole host of different but serious adverse effects that we can manage. But we need to intervene early.

We need to check on these patients and do a lot of the education and bring them back for visits, which was never what I did with endocrine monotherapy. Now we’re like, “We need you to come back. We need you to do a check for CBC [complete blood count]. We need you to…look at the patient’s RAP [right atrial pressure].”

Part of it is managing toxicities that we clearly want to be adept at. The other key part is if we don’t manage these toxicities, we’re not going to get compliance, and those patients are going to be out there and self-discontinue and not make us aware, and I think that’s the key. I do that lecture up front with the patient. We may have some bumps in the road until we get the right dosing, the right combination of medications, to support you through this partnership, but it’s pivotally important because it’s in compliance for you to gain and derive that benefit or a chance at that benefit.

We’ve got to do our best to make you able to tolerate any of the toxicities that come along, so you can be an equal partner in doing your part, in being able to manage the compliance aspect when you walk out of the door. It’s a lot more education for myself when I’m face to face with the patient, as well as for the staff when they’re answering those phone calls. These are different times when a patient is on an endocrine combination backbone therapy vs endocrine monotherapy.

Certainly, some of the nurses were like, “Oh, you want this to PCP.” I’m like, “No, I want that patient in our office.” But they’re used to it, and it’s a lot of education just trying to break that habit and practice patterns.

 Yeah, it’s really a change. It’s a complete change. It’s so important though, as you say. Tiffany, what has been your experience? Many patients with weight loss, a need for dose reduction. Patient selection?

 The key about education in managing expectations is that it can’t be overemphasized. Being sure our patients are aware of what to call about. Being sure they’re aware of diet and glucose monitoring. The rash, in my experience, has been easily mitigated with the use of the prophylactic antihistamines. What I feel like I’m learning is how to be an endocrinologist, how to manage and monitor blood sugars, and how to educate about that. To your point, being sure that our nurses are informed because they’re doing a lot of this frontline work as well and responding to our patients and really keeping them safe at home.

Mitigating these adverse events is important. For me, it’s a learning curve, as it is with many of our new drugs when they enter into our armamentarium. We’ve become cardio oncologists, and now we’re becoming endocrinologists or at least becoming familiar with blood glucose management.

 Thank you. I just want to reiterate what Hope said about patient selection. I tried to cheat a little and have the hemoglobin A1C be 6.5 g/dL or above. It just doesn’t work. People got way too much in the way of hyperglycemia. I think they had tried that in the SOLAR-1. It didn’t work, which is why they said less than 6.5%. It just really has to be that way, taking the time to get their glucose into good control really has to happen. Otherwise it just won’t work.

Then I max out metformin, first as they get their blood glucose above 160 g/dL. I’m monitoring them closely. The home glucose monitors are very inexpensive and easy to do. Write it down, take it a few times a day. As Hope said, it’s just the first few weeks you have to do it. I do go to the SGLT2 inhibitors because they lower insulin; anything that lowers insulin is going to help alpelisib work better and longer.

That’s low carb, the low sugar, and exercise. Basically, metformin lowers insulin, and SGLT lowers insulin inhibitors. I’ve been able to manage it, as I said. I have had some patients who need a dose reduction for excessive weight loss, but then it stopped. Now they’re able to just sail along. I must say, I’ve been impressed with the level of activity.

 It’s interesting too, and you commented on this. What has happened early when people don’t have experience is that they give the patient alpelisib, and then they come back 2 weeks later and they get ketoacidosis and hyperglycemia. Having these proactive approaches is really important. I actually think that what we probably should be doing is prophylaxing in patients, in some way or another, who have these slightly elevated hemoglobin A1Cs.

You can take 2 weeks to better control somebody’s glucose and talk to them about diet and management before you even start. They don’t have to come in at day 8, but you have to check. Having an endocrinologist on speed dial helps a lot with e-consults and things like that; that helps. I find that they generally take a little less of an aggressive approach, but the other thing that’s really important is that if you hold the alpelisib, these pills have a short half-life unlike say tamoxifen.

The hyperglycemia goes away with the flick of an eye, so now you have to be really careful because if you have them on a long-acting hypoglycemic agent, you can cause severe hypoglycemia. You want to stop everything within 24 hours that you’ve been doing if a patient didn’t need it before.

 Yeah, that’s super. It’s good if somebody gets really high on their glucose. Just stop it, and in 36 hours, they’re back down to normal.

HER2+ MBC Adverse-Event Management

 I want to ask Denise and Tiffany. First, I’ll say that we got the 

, and that’s 40% of our ER [estrogen receptor]–positive patients. Upstream from 

 is mutated in only a tiny fraction of ER-positive patients, but it is part of that whole signaling from a whole bunch of receptor tyrosine kinases that can drive resistance to endocrine therapy. It’s been the target of several trials going on with capivasertib and ipatasertib, 2 AK inhibitors.

We saw randomized phase 2 data and the FAKTION trial looking at unselected patients, ER-positive patients with breast cancer who had progressed on an aromatase inhibitor. Prior to the CDK4/6 availability, fulvestrant plus or minus the capivasertib, and we saw very nice improvement in progression-free survival, regardless of 

-mutation status. That’s in the CAPItello-291 larger phase 3 trial. We’ll have to stay tuned, but it’s a very nice trial for our patients. The AKT inhibition may be coming for certain patients, but we still have everolimus in our practice.

I want to hear from Tiffany and Denise. How are you utilizing everolimus in your practice now. Tiffany, how are you using it?

 Similar to what you had said earlier, we need to understand what the PI3 kinase status is of our patients with hormone receptor–positive advanced breast cancer. That is something that, through cell-free DNA or tissue sampling, we understand. For my patients who are progressing on a CDK4/6 inhibitor who failed to have a biomarker to predict benefit from alpelisib, I still consider the combination of aromatase inhibitor and everolimus.

It tends to be a bit later in my sequencing, but I’ve found it to be much better tolerated with the help of the SWITCH study and the use of oral topical steroids to help reduce the mucositis. I still find it as a tool in my armamentarium, particularly now in those patients who failed to have the 

 I really echo what Tiffany says. I still use it, but not as frequently in the past when that was the only targeted endocrine therapy doublet out there, prior to the CDK4/6 inhibitors. It has moved to a later line, but when I think about where these patients are with their disease struggles and what my choices are to treat if they don’t have a 

 kinase mutation. I can’t think about adding an agent to an endocrine partner. I look at everolimus and feel very comfortable managing that combination.

Addressing dexamethasone and SWISH and the potential of the stomatitis and mucositis in those patients, at every juncture we look at what that progression looks like in that particular patient and the status of their disease in multiple disease sites. The thought continues to be trying to prolong their treatment on therapy endocrine partner, which has been the main signaling of hormone receptor–positive breast cancers, before I move onto sequential single-agent chemotherapies. That’s definitely integrated in that sense.

I still think the driver for many of the hormone receptor–positive diseases after metastatic disease states, after CDK4/6, is still best addressed by an endocrine therapy backbone partner. But eventually those patients slide into the need for cytotoxic chemotherapy. I tried to delay that as long as possible and use all other tools available.

After Progression on PIK3CAi Therapy: MTOR Inhibition

 I want to transition to something we can definitely use after progression on CDK4/6, and that is alpelisib. First, we’ve got to find the right patient population. I’ll say a few words about looking for and finding the patients with the 

 mutation in their breast cancer. Then we’re going to turn it over to you, Hope, to update us on your really nice data, the BYLieve data, from ASCO [American Society of Clinical Oncology Annual Meeting].

This is put against the need for NGS [next-generation sequencing], as Denise said, on the map. We’ve got to find these patients with ER [estrogen receptor]–positive, 

 [human epidermal growth factor receptor 2]–negative metastatic breast cancer, whose breast cancers have a 

 mutation. You know it’s a truncal mutation that happens very early in the development of primary breast cancer.

By and large, if you look for it in the primary breast cancer, you’ll find it in about 40% or so of patients. In the metastatic setting you should find it, and about 40% of patients. Many of us biopsy the first recurrence. Sometimes we don’t get that much tissue. It’s not that easy to assay for NGS all our metastatic biopsies. Here we have our patients; they’re on a CDK4/6 inhibitor, and we need to be thinking about what the next step is for those patients.

And we need to see if alpelisib is going to be an option, so many of us will get ctDNA [circulating tumor DNA] on those patients either upon their initial presentation with metastatic disease or upon progression on a CDK4/6 inhibitor. In data from the SOLAR-1 trial, which was fulvestrant plus or minus the alpelisib, only 6% had a prior CDK4/6 inhibitor, hence the larger experience that Hope found from the BYLieve trial. We found in the SOLAR-1 that patients in the metastatic setting, in whom circulating tumor DNA identified the 

 mutation, did marvelously well with very large separation in the progression-free survival curve. That was very impressive. If we do find 

 mutations in ctDNA in our metastatic patients, that’s a great patient for alpelisib.

If we don’t find it in the circulating tumor DNA, I certainly go back to the patients’ primary breast cancer, and I test it there as well. The NCCN [National Comprehensive Cancer Network] really does recommend that particular algorithm. If I don’t find it in either place, I will check for it again further down the road in the metastatic setting because the PALOMA-3 trial—which gave fulvestrant plus or minus palbociclib—got ctDNA before treatment and upon progression found about 10% more patients had to PIK3CA mutation upon progression on a CDK 4/6 inhibitor.

I’ll keep looking because over time, as Hope said, they’ll be more clonal heterogeneity that evolves, and you might still be able to help the patient. It’s been pretty easy to find the patients with the 

 mutations. Hope, what do we do with those patients who are progressing on CDK4/6 inhibitors? Tell us about the BYLieve data that will help us understand who will benefit from alpelisib.

 These are really fascinating data. Alpelisib was first approved based on the data from SOLAR-1 where patients who had progressed on an aromatase inhibitor had to receive fulvestrant and were either placebo or alpelisib, and then the 

-mutant cohort. The median progression-free survival was almost doubled with a hazard ratio of 0.65, leading to regulatory approval of alpelisib.

The big issue is that SOLAR-1 was enrolled completely before CDK4/6 inhibitors were really approved in most places. We really didn’t have enough data to know how alpelisib would work in this situation; 20 patients in SOLAR-1 had prior CDK4/6 inhibitor treatment. In that group with 

 mutations, the median progression-free survival went from 1.8 to 5.5 months, in such a tiny group of patients.

We designed the BYLieve trial with the idea to really treat those patients. At ASCO we presented cohort A; there were 3 cohorts. The third cohort after chemotherapy is still accruing. The second cohort hasn’t reached the 6-month landmark. In the cohort we presented, patients had to have progressed on a CDK4/6 inhibitor and an aromatase inhibitor as their immediate prior treatment.

Then they were all treated with alpelisib and fulvestrant. They all had to have a 

-positive disease. Our final analysis of these data included patients who also had central confirmation of 

Hope S. Rugo, MD, FASCO, UCSF Helen Diller Family Comprehensive Cancer Center

Articles

Using CDK4/6 Inhibitors After HR+ mBC Disease Progression

Case Discussion: Resistance to CDK4/6 Inhibitors in HR+ mBC

Implications of PIK3CA Mutations in HR+ mBC

Selecting a CDK4/6 Inhibitor for HR+ mBC

Using CDK4/6 Inhibitors in First-Line Treatment of HR+ mBC

Updated Data for Metastatic HER2+ Breast Cancer

Prognostic Tools for Early-Stage HER2+ Breast Cancer

Current Treatment Landscape for HER2+ Breast Cancer

Notable ASCO Trial Updates

HER2+ MBC Adverse-Event Management

After Progression on PIK3CAi Therapy: MTOR Inhibition

Significance of PIK3CA Mutation in HR+ Breast Cancer

Mechanisms of Resistance to CDK4/6 Inhibitors

CDK4/6 Meta-Analysis Data

CDK4/6 Clinical Trial Survival Data Impact

CDK4/6 Inhibition in HR+ Metastatic Breast Cancer

Next-Generation Sequencing: Triple Negative Breast Cancer

Phase 3 ASCENT Regimen Accelerated Approval

SWOG S1416 and TBCRC 048 Phase 2 Trial Overviews

ASCO New Data: PARP Inhibitors