Burgeoning Breast Cancer Landscape Brings Hope for a Brighter Future

Bhuvaneswari Ramaswamy, MD

The expansion of HER2-directed treatments and formulations, the availability of CDK4/6 inhibitors, and the broad activity of sacituzumab govitecan-hziy (Trodelvy) is a testament to the successful development of personalized medicine in breast cancer, explained Bhuvaneswari Ramaswamy, MD, who added that awareness and action regarding the disparities that still exist is necessary to ensure all patients are able to reap the benefits of these therapies.

“The number of novel therapeutics coming up is just shocking and is absolutely a triumph. It’s not at all possible without this collaboration for us with the pharmaceutical companies, academic institutions, researchers, the [National Cancer Institute] and other sponsors, but most importantly, our patients who are willing to enroll on trial. Without them, we wouldn’t be where we are. Patients are equal partners in this collaboration,” said Ramaswamy.

However, she added, there are still disparities among molecular subtypes and certain sites of metastatic disease, some histological subtypes, and even rare cancers, such as metaplastic cancers. We see those patients and we still take the data from [their subtype] and treat them [the same] just because they’re less in numbers, but for that individual patient, they’re still not getting tailored therapy,” added Ramaswamy.

The OncLive® Institutional Perspectives in Cancer webinar on breast cancer narrowed in on changing standards in HER2-positive breast cancer, hormone receptor (HR)–positive, HER2-positive or -negative breast cancer, triple-negative breast cancer (TNBC), and also changes regarding immunotherapy.

Ramaswamy, who is section chief of Breast Medical Oncology and director of the Medical Oncology Fellowship Program in Breast Cancer at The Ohio State College of Medicine, The Ohio State University Comprehensive Cancer Center–James, and cochair of the meeting, discussed the nuances of therapy selection in breast cancer across histologies as key highlights from the event, and also anticipated research on the horizon.

OncLive®: At which point do patient factors play a greater role in terms of treatment sequencing in metastatic HER2-positive breast cancer?

Ramaswamy: Patients with HER2-positive breast cancer really have so many treatments at this point, which is great. We need to be grateful for those patients, and of course, for the breakthrough research. Beyond that, we look at the data and what has impacted overall survival [OS], because that is still the gold standard for all of us. We also consider which treatment approach would benefit a certain patient population; it’s a combination of factors [that cater to] individual patient needs.

Pretty much all of the [breast medical oncologists] are using the taxane, trastuzumab [Herceptin], and pertuzumab [Perjeta] combination as first-line therapy because of such strong OS data. Many of us are still probably using ado-trastuzumab emtansine [TDM-1; Kadcyla], our antibody-drug conjugate [ADC] in the second-line setting as well.

Beyond this, [patient issues become much more important]. If someone has central nervous system metastatic disease, then we may lean towards tucatinib [Tukysa] and for someone who has a cardiac issue and cannot use trastuzumab, neratinib [Nerlynx] plus capecitabine is a nice option.

Some patients cannot take pills, and for those patients, we may lean toward one of the other ADCs like fam-trastuzumab deruxtecan-nxki [Enhertu]. We now also have the option of using margetuximab[-cmkb (Margenza)] in combination with chemotherapy. In every comprehensive cancer center, we’re also looking at clinical trials, because we have newer drugs that are coming down the pipeline, such as newer ADCs, and we’re trying to see whether those agents could come into play as well, at every point of progression.

Will intravenous [IV] trastuzumab and pertuzumab continue to play a role in HER2-positive breast cancer now that the subcutaneous [SC] formulation, which may be more convenient for patients, is approved?

Now we are getting into the nuances; we know what drugs work. Now we are looking at convenience delivery issues, and what would suit a patient better. The SC injection of pertuzumab and trastuzumab has given us another option. I do not think of it as a replacement for IV therapy for everybody, because there is a role for both. Some patients have gotten into the habit of coming in and getting their treatment and are happy with that approach. There are others who do not want to have a port, who do not want to spend as much time here.

Whether this administration can be administered by health care professionals at home [has yet to be determined], but that could help avoid people coming in every 3 weeks. This is going take a little bit more time. I also worry about the cost that comes along with that. I certainly think it is something that we can discuss with our patients and see whether this will be an appropriate option for them, which is wonderful. In the future, if the financial cost of this approach comes down a little bit, it can be helpful for more patients, and, globally, it could be very valuable.

Shifting to metastatic HR-positive, HER2-negative breast cancer, what data are you using to guide treatment selection among the 3 approved CDK4/6 inhibitors?

[These agents] have changed the lives of patients with metastatic HR-positive breast cancer, and I see it every day, and over the years, how long these patients can stay on this first-line therapy. For a patient, that is huge. [These agents give them] hope. Patients are not changing treatment within 3 to 6 months [of their first therapy]. [These agents] have changed the landscape for our patients, and for that we should be grateful.

As far as how we use these 3 agents, there is a higher use of palbociclib [Ibrance] than other drugs for many reasons. First of all, that agent has been in the market longest, so there is that comfort, and the ease of knowing a drug, both from the prescriber perspective, and from the insurance perspective. Of course, it’s extremely well tolerated.

I do look to ribociclib [Kisqali] for a patient who is premenopausal because of the survival data. Also, ribociclib has an advantage because if you dose reduce, you don’t have to waste the previous prescriptions because they can use the same prescription to reduce their dose. Based on insurance and the funds that are available for the patient, that may be another useful option.

I use abemaciclib [Verzenio] in a patient for whom I worry about myelosuppression. Abemaciclib causes less [myelosuppression], and I’ve seen it be very helpful in that situation. I have also used abemaciclib as a single agent, and I’ve seen some really surprisingly good responses, yet again, showing that these drugs have so much value. Patient scenarios affect our choice. Although, our familiarity with the drug that we use more often does sometimes dictate the choice that we pick.

Will CDK4/6 inhibitors move into the adjuvant HR-positive, HER2-negative setting?

Yes. With the data from the monarchE trial with adjuvant abemaciclib data, there is starting to be hope. We’ve had some negative trials in this space, based on the PALLAS [NCT02513394] andthe PENELOPE-B [NCT01864746]trials. The patient populations are a little bit different across these 3 studies; they’re not hugely different, but a very high-risk population is what we need to really focus on.

I do believe those high-risk patients have micrometastases. This is where I think we could make an impact on adjuvant CDK4/6 inhibitors. We do need longer follow-up, even on the monarchE trial, we need to see a little bit more data for us to be sure that this is a sustainable response. The CDK4/6 inhibitors could be slightly different, but we don’t know. I hold out hope that in a properly selected high-risk population, adjuvant CDK4/6 inhibitors are going to make some difference.

How can genomic information further improve personalized therapy for patients with early-stage HR-positive breast cancer?

Genomic testing has changed the landscape of early-stage HR-positive, HER2-negative breast cancer. We use so much less chemotherapy [because of it], and, overall, that has saved so much toxicity for patients [and perhaps even some of their lives]. We have to remember that there is still a mortality risk [in this setting].

We use genomic testing very frequently in our practice. It’s very important that in appropriate patients, we do that. We’re still in a little bit of a flux in those intermediate-risk patients, particularly in premenopausal patients less than 50 years of age. I do believe that part of the chemotherapy benefit is coming from putting these patients who are close to 50 into menopause. I would think that ovarian suppression may be able to give us that advantage. Do I have data to prove that? I don’t. We’re still looking for more data from the RxPONDER trial [NCT01272037].

These genomic tests have also shown us that chemotherapy can still be very helpful for many patients. These studies show us that these treatments that we’ve used for so many decades are still very important in the care of HR-positive patients.

Can we pick the high-risk patients who may benefit from CDK4/6 inhibitors from this data? It’s a little too early to tell. In the metastatic setting, we are starting to also use next-generation sequencing earlier on to understand what the somatic mutations that these tumors carry are to see whether there is a PIK3CA mutation and down the road, whether there’s an ESR1 mutation. These really are changing the way we are treating patients and tailoring therapies for them.

Moving to triple-negative breast cancer (TNBC), could you speak to the impact that sacituzumab govitecan has had on the paradigm?

Finally, we can say we have some kind of targeted therapy for TNBC. We do of course have the PARP inhibitors, but it’s still in very select patients. Thankfully, sacituzumab govitecan can address most patients with TNBC, and we don’t need a specific biomarker, which is excellent. [The agent has shown] very exciting data, and I’m so glad that we now have this option for our patients. The agent has become not just a third-line option, but also earlier on in treatment as a potential option, and possibly has some impact in the central nervous system. Patients tolerate the agent reasonably well. Myelosuppression is an issue, but patients tolerate it reasonably well.

I am looking forward to future combinations with targeted therapies to see whether that can improve outcomes even further. I’m hoping this is the first step towards identifying such common proteins that may be expressed by TNBC to determine how we can improve drug delivery into these cells. Maybe that would be a new paradigm in TNBC. There may not be a novel target to directly target [these proteins], but there may be a target that can improve drug delivery. I’m really excited for the future.

Looking to the future, what combinations could lead to promising treatment strategies?

We’ve been working on the PI3K pathway and how to target that in breast cancer, and now 2 drugs are approved in the HR-positive setting. That is definitely a pathway that increases the growth kinetics of these tumors and makes them more aggressive. I’m looking to see whether it is up at the PI3K level, or it’s going to be at the AKT level that we can drug these targets. I definitely think it’s going to be with some kind of chemotherapy backbone.

I’m really looking to see whether with an appropriate target in this pathway with the chemotherapy combination we will see some excellent new opportunities. Maybe those are things that we could use, even if the patient does not have a PD-L1–positive tumor. Perhaps this is the first-line therapy that we would use.

I’m also excited about the new ADCs. We have already shown that [sacituzumab govitecan] works, so I’m hopeful we’re going to see more of those agents.

Right now, other than giving some patients immunotherapy, we just give one chemotherapy after the other. Instead, maybe we could intervene with some of these combinations, which may cause more prolonged responses. That is the key, and that’s where these patients start to feel the frustration compared with patients with HR-positive or HER2-positive disease; their responses are not sustainable. These kind of targets with cross-resistance could help us provide more sustained responses.

PD-L1 has become a critical biomarker with therapeutic implications. How would you summarize the implications of not testing for the marker?

It’s essential that we test every patient with metastatic TNBC for PD-L1. The question is: Which tumor tissue do we test? Bone may not be the appropriate tissue to test for PD-L1 status. What about the primary tumors? Many of these trials didn’t use the primary tumor PD-L1 status to [direct] treatment.

If we don’t know their status, and we don’t look for it, you may have lost an option. We also understand that these treatments are better given earlier in their metastatic journey, and if you start chemotherapy, you could miss a treatment. Even though the responses are not as robust as we would like, those responses are still, for those who have a response, are very sustained. To lose out on that opportunity is inappropriate.

PD-L1 is something that we need to test just as you need to make sure that BRCA mutations are tested for because that allows them another targeted therapy option. There are clinical trials that combine a PARP inhibitor with a checkpoint inhibitor, and you will lose options if you don’t look for it. It’s very critical.

What is your hope for the future of immunotherapy in breast cancer?

In breast cancer, we may start to see some interesting findings through the other immunomodulatory approaches, whether that is combining things with the TNF factors, and approaching 2 immunomodulatory molecules and vaccines. It’s an area that we’ve been working on for a long time. But our understanding has improved so much, and our delivery of these agents have improved so much. It seems still a little bit of a difficult to reach point, but I have some hope for these alternative immunomodulatory approaches in breast cancer in combination. We should have some hope for all of these.

It’s a big step for us, but it’s a step that we should not ignore. In general, breast cancer is not an immune rich cancer. It’s not that easy to figure out immunomodulatory approaches to change the cancer outcomes, but I don’t think it’s a place that it doesn’t play a role. We’ve proven that that’s not the case. We just need to understand it better. I do that we’re going to see more in the next decade regarding immunotherapy in breast cancer, but not just necessarily of the checkpoint inhibitors, but other ways of changing the tumor microenvironment with other approaches.

How has collaboration contributed to the advances we’ve seen, and how can it contribute to gaps in patient care in the future?

Another thing to remember is that disparities still exist. We still are very much not doing a great job at minority accruals; we need to do better. We’re still taking the data largely from Caucasian patients and using it for the rest of the world. We still also have some disparities across different molecular subtypes of breast cancer. Patients with brain metastases, particularly leptomeningeal disease, [need to be kept in mind] because, although they’re living longer, it’s certainly not enough. We need to do more. We also need to think about lobular cancers. Sometimes they’re left behind. It’s so hard to get these cells to die; they just keep quiet and then wake up later. How do we attack those dormant cells?

I don’t want to forget male breast cancers, which has absolutely taken stuff from female breast cancers. The problem is difficult to solve, but maybe as an international community, we can do better if we bring data on these rare situations together and do better for these patients.