Dr. Adam Brufsky:
Welcome to The ASCO Post Roundtable Series on PI3K Inhibition Strategies for Hormone Receptor–Positive, HER2-Negative Metastatic Breast cancer. My name is Dr. Adam Brufsky. I am a Professor of Medicine at the University of Pittsburgh, a breast cancer oncologist, and a member of the UPMC Hillman Cancer Center. With me today, we have Dr. Heather McArthur. Heather, do you want to introduce yourself?
Dr. Heather McArthur:
Certainly. I'm the Professor of Medicine at University of Texas Southwestern in Dallas, Texas, and the Clinical Director of the breast cancer program here. Thank you for including me.
Dr. Adam Brufsky:
Great. And we have Dr. Seth Wander. Seth?
Dr. Seth Wander:
Great to be with you both. I am a medical oncologist at the Mass General Hospital in Boston and Assistant Professor of Medicine at Harvard Medical School.
Dr. Adam Brufsky:
Okay. And so our final installment will focus, I think, on really what is going to be a serious conundrum in the not too distant future, and that is progression after adjuvant treatment with a CDK4/6 inhibitor. So let's start with the case. This is a 42-year-old woman who presents with bilateral breast cancer, both of which are ER positive. In both of them the ER is 50%, PR 25%, HER2 1+, and they're both grade 3.
She's germline BRCA2 positive, so she gets a bilateral mastectomy and subtle lymph node biopsy. Her right breast has a 2.5-cm infiltrating ductal carcinoma with the same pathology as above with one of three sentinel nodes positive. The left breast has a 1.5-cm infiltrating ductal carcinoma with two of four sentinel lymph nodes positive. She's given dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks and postmastectomy radiation to both sides.
Kind of rough. But anyway, what's the next step? What would you give her and how would you manage her? Let's start with Heather. So this is someone who has germline BRCA2 mutation, and she has high-risk features. So what do you do?
Dr. Heather McArthur:
I mean, this is such an incredibly difficult case. So I think it goes without saying that we would give this patient our best available endocrine therapy in the form of ovarian suppression with an aromatase inhibitor. Because of the bilateral nodal involvement, a CDK4/6 inhibitor would also be part of that regimen. And you could offer either abemaciclib or ribociclib.
In my mind, I don't see any contraindications to either medication here. The question in my mind is really whether you offer olaparib. I mean, technically, she would have qualified for the OlympiA study of adjuvant olaparib, which, of course, didn't allow for adjuvant CDK4/6 inhibitor and vice versa, and how do we reconcile these data sets where we see an overall survival advantage with adjuvant olaparib in patients with established or suspected BRCA mutation.
So I would probably, because she's so high-risk, she's so young, she's got bilateral breast cancer and they're both node positive, I would be tempted to give olaparib prior to CDK4/6 inhibitor in this specific case. But that would be a very unusual situation.
Dr. Adam Brufsky:
Right. And just to remind everybody, the label on adjuvant abemaciclib is within 3 months of endocrine therapy or 18 months of surgery. So you can use either one. With ribociclib, adjuvant ribociclib, is within 12 months of endocrine therapy. You could be on endocrine therapy for 12 months. Seth, how would you handle this?
Dr. Seth Wander:
I agree with the great points that Heather just made. This is a very high-risk patient for the reasons that we're talking about. And the theme I think of our conversation today is our arsenal is becoming more complex and broader. We have new targeted therapies that are moving into different patient populations. It's a good problem to have for patients and clinicians.
And here's a patient I'd want to reach into our toolbox as far as I could and think about all the things that Heather just mentioned. I agree. I would sequence. I would not obviously give a PARP inhibitor and a CDK inhibitor together. We don't have safety data for that, and there would be risk of compound cytopenias and other toxicity. Because of the survival data for the PARP inhibitor, I would probably sequence that in first and then go to adjuvant CDK blockade after.
I'm curious what you two think. I mean, we're getting more and more mature data from NATALEE. I tend to err on the side of abemaciclib because we have more data for the overall population when they've all been off of abemaciclib now for more than 2 years. The magnitude of iDFS benefit has not only persisted, but actually expanded over time with everybody off of drug.
I'm hopeful that the NATALEE curves will continue to show the same pattern there, and that they'll be interchangeable and it'll depend on patient characteristics and other factors. But I agree. I would start with PARP. Go to CDK. Optimize adjuvant antiestrogen therapy with ovarian suppression and extended-duration AI.
Dr. Adam Brufsky:
All right. So she's given LHRH agonist anastrozole and abemaciclib at 150 milligrams PO BID. So a couple of weeks later, she develops grade 2 diarrhea. So they hold the dose. She's given antidiarrheals, and she's dose reduced 100 mg by mouth twice daily. And we do know from the data, I think, I don't remember where this was presented, I think it may have been just published last year, that actually you can dose reduce abemaciclib and get the same efficacy.
The hazard ratios remain the same. I think it was published last year in NPG Breast Cancer. But nonetheless, they do that. She tolerates her 2 years of abemaciclib, and we continue the LHRH and anastrozole. 11 months after completing—this is important, it's 11 months after completing her adjuvant abemaciclib—she complains of back pain.
CT scan of the chest, abdomen, and pelvis shows three lung lesions, the largest 1.5 cm, and three lytic lesions of the thoracic spine. You biopsy the lung lesion. She's got adenocarcinoma that's poorly differentiated, ER 30%, PR 30%, and she's asymptomatic. What next? What would you guys do next? Heather, you want to start?
Dr. Heather McArthur:
I mean, this is obviously another really poor-prognosis situation with progression so early on in the adjuvant course and so soon after completion of adjuvant abemaciclib. I would biopsy one of the distant metastasis as they did here. I'm a little concerned because the hormone sensitivity seems to be diminishing. I would do NGS on the lung biopsy here, and I would use that information I would hope to inform next steps at this juncture.
Dr. Adam Brufsky:
Seth, any comments?
Dr. Seth Wander:
Yeah, a couple of broad comments here. This is, of course, as you mentioned, Adam, is going to become an increasingly common problem for us because we're now deploying CDK4/6 inhibitors across a broader population of patients. We have so much to learn about what the molecular and genomic alterations are. We've done a lot of work, our team and many others, in looking at the genomic factors that correlate with CDK4/6 resistance in the metastatic setting.
One obvious question is, are we just moving it earlier? Is it the same pattern of these very heterogeneous alterations in RB, aurora kinase, cyclin E, AKT pathway, RAS pathway, FGFR, HER2, loss of ER we've also identified previously, or are there other things we're finding in this population? From a clinical standpoint, I'm thinking of this conceptually the same way we think of endocrine resistance.
I think we're going to be able to bucket these patients into several different clinical groups. Right now we're seeing very few of these patients, but these are the ones who are progressing either on or shortly after adjuvant CDK therapy. There may be other patients who have some intermediate length of time, like a couple of years. There may be other patients who go 10 years after finishing their adjuvant CDK inhibitor and recurring.
And of course, the way we clinically approach those and likely the molecular features of those tumors are going to differ. So at the moment, we haven't had enough time to see those other groups of patients start to pop up in the same way we think about treating patients who used to progress on adjuvant endocrine monotherapy. But to Heather's point, I definitely would want to go for sequencing here.
I'm really hoping we see something targetable pop up. We know we have the BRCA mutation in this case. We talked about using the adjuvant PARP, but I think this patient didn't get it, so that's going to be a treatment option. We also have implicated AKT pathway, RAS pathway alterations. If this patient had an AKT or a PTEN alteration that drove the resistance to the CDK4/6 inhibitor, I would also be very enthusiastic about thinking about something like capivasertib here.
Dr. Adam Brufsky:
Got it. So we do a liquid NGS and she's got an AKT mutation, the most common one, which is the E17K. And obviously she's got a very high allele frequency of BRCA mutation because she's mutated. So she's got a BRCA2 truncation mutation. That's seen at an allele frequency of like 35% where the AKT is maybe 1%. So now, Heather, what would you do? You have a positive NGS for AKT in this setting. What's your next step?
Dr. Heather McArthur:
So we have options. The most obvious options are either targeting the BRCA mutation and we know from OlympiA and other studies that earlier on that you apply PARP inhibition, the more likely it is to be successful. We also have the AKT mutation, which allows for access to the capivasertib-fulvestrant combination and of course, chemotherapy and ADC therapy would be an option.
I think at this juncture, having just been exposed to one hormone therapy, my bias would be to pursue endocrine therapy before moving on to chemotherapy or ADC therapy. I'd be a little concerned given the pace of disease using monotherapy in the form of a PARP inhibitor here. So I would probably favor dual therapy with capivasertib and fulvestrant.
Dr. Adam Brufsky:
Got it. So in fact, that's what she gets. She gets fulvestrant and capivasertib with cetirizine 10 mg daily as prophylaxis for rash. Some people do that. And she gets obviously zoledronic acid every 3 months for her bone metastases. She tolerates it well. Her highest fasting glucose is 120, and initially, her lung lesions improved and the bone lesions turned sclerotic.
But again, after about 12 months, which is a long time for this, obviously the median PFS of this is a lot shorter than that, but after about 12 months, her lung lesions now progressed to six, with the largest one being 3 cm. So Seth, do you repeat the NGS now? Do you rebiopsy? Do you consider an FES PET to see whether she's still got endocrine-sensitive disease? What do you do at this point?
Dr. Seth Wander:
You know my bias with the sequencing, Adam, so yeah, I definitely would repeat sequencing here. This is actually an interesting tumor genomic environment, right? We have BRCA alterations. We have emerging data from the team at Memorial Sloan Kettering looking at the impact of BRCA alterations on CDK sensitivity. We have this newly acquired AKT mutation, again, likely under selective pressure on adjuvant CDK 4 blockade.
To Heather's point, we could have gone either direction here with the AKT alteration or the PARP inhibitor. I would repeat, again, to try to figure out whether there are other targetable alterations. We don't yet have an ESR1 mutation in this patient. I'm not sure I would rebiopsy again unless I thought that there was some area of the tumor behaving differently or unless we had a HER2 true zero.
And we're looking to understand if we could think about HER2 low situation in the future. The FES PET is a really interesting question. This is an exciting new imaging tool where we're actually looking at the degree of ER activity across different tumor sites in the body in the same way that FDG utilizes glucose. The problem with the FES PET now is the washout that's required depending on which drug you use.
And when you use an injectable SERD, it's quite a long washout, I think on the order of four to six plus weeks. And that obviously would be prohibitive in a patient with aggressive disease with features like this. So the good news with the FES PET, as we're moving toward the oral SERDs and some of these newer oral agents, the washout is much faster, and I think it's going to continue to be an interesting test that we can start to utilize.
So I probably would repeat an NGS. I'd be thinking strongly about targeting that BRCA alteration for the discussion we've been having here, because this is again, a personalized therapy for this patient. I'd be looking at clinical trial opportunities with novel agents in the CDK AKT inhibitor resistant setting. And in the back of my head, I'm also starting to think about an ADC or chemo depending on how things go in the next line of therapy.
Dr. Adam Brufsky:
Got it. So she gets a liquid NGS and now she's still got the AKT mutation and the BRCA truncation, but now she has an ESR1 Y538S. So Heather, what do you do now? She's been on a PI3K and fulvestrant for I think 9, 10 months, and now she's developed an ESR1 mutation. So what do you do? And she's not had olaparib either yet. So you've got a bunch of options available to you.
Dr. Heather McArthur:
And it's a bit of a six of one, half a dozen of the other, right? Because we don't have data to inform the space where patients have access to both types of agents. ESR1 being an acquired mutation, and we don't know what the impact is of subsequent lines of therapy on acquired actionable ESR1 mutations in a modern treatment era. So my bias would probably be to try and exploit that while it's available. It's one of the three most common mutations that's been identified here.
So that would probably be my bias to exploit that while it's available, knowing that that BRCA mutation will remain constant over time. But again, it's six of one, half a dozen of the other. I'm really only considering that because I'm shocked by this patient who progressed within nine months of first line therapy, but then had 18 months of durable response to targeted therapy. So that bolsters my interest in further trying to exploit targetable mutations in this patient.
Dr. Adam Brufsky:
Got it. Seth?
Dr. Seth Wander:
Yeah, as Heather said, I think you're going to get several different answers from multiple breast oncologists. And Adam, I know you're participating with us looking at this real-world experience with elacestrant. To Heather's point, the real-world data that we've generated in collaboration with our partners at Guardant has been quite interesting. We actually see real-world estimates of time-to-next treatment or progression-free survival on the order of 6-plus months, even in later lines of therapy like this one.
So certainly if the patient was clinically stable, she'd been doing well for quite a long time on her prior therapy, there wasn't imminent visceral risk here, it wouldn't be, I think, crazy to try a next-generation antiestrogen-based therapy, either standard of care or if there was an available doublet on clinical trial. But still, I definitely want to get this patient a PARP inhibitor at some point. So we all, I think, agree on that. It's just a question of when is it going to be.
Dr. Adam Brufsky:
Got it. So I mean, if she were regress on this and say she's still relatively stable, would you guys be thinking of olaparib at that point? The decision to me would probably be olaparib or an ADC, and I think that would really probably depend on her clinical picture. I mean, would that be your guys' thought process as well?
Dr. Seth Wander:
I would try to exhaust all personalized available, well-tolerated oral options, including everything that Heather brought up previously before I went to the IV ADC.
Dr. Heather McArthur:
Even if it conferred only 3 months progression-free survival, that would be clinically meaningful, so 100%.
Dr. Adam Brufsky:
Got it. All right, guys, this has been great. The key clinical takeaways, I think, are with high-risk BRCA2 associated breast cancer, the choices will be adjuvant olaparib, adjuvant CDK4/6, or even both, and how we sequence them is still a matter of some question. Progression within 12 months of an adjuvant CDK4/6 inhibitor could be treated as first-line ER positive disease or second-line ER positive disease as well.
I think next-generation sequencing at that point would be essential in sorting out the need for targeted therapy. Capivasertib can be used with AKT mutations in the absence of PI3K mutations. And I think treatment after progression with the PI3K, as we discussed, in the second line and third line really depends on the next-generation sequencing results, the pace of disease, prior therapy, the bulk of disease, and patient comorbidities.
So with that, again, I want to thank you all very much. I thank both of my panelists who've done a great job. This brings us to the end of this case, and please see other segments for further discussion about the latest research in metastatic hormone receptor–positive, HER2-negative breast cancer, or visit ASCOPost.com. Again, thank you all very much for listening to us and hope you learned something. Thank you.
