Strategies for Managing Patients With Advanced Breast Cancer

With the release of new data, treatments for patients with breast cancer and the guidelines surrounding it change to reflect what is newly available. In breast cancer, the subgroup that has seen the most data leading to new disease management reccomendations has been estrogen receptor (ER)-positive disease.

Over the past decade, treatment options for this patient population have changed due to new developments. Where there was once only endocrine therapy alone, there are now various options for the management of care including CDK4/6 inhibitors like abemaciclib (Verzenio) or PARP inhibitors, specifically olaparib (Lynparza).

Another area that is evolving for patients is the use of checkpoint inhibitors as a treatment for early-stage breast cancer for higher risk patients. Trials with pembrolizumab (Keytruda) have shown that this in addition to chemotherapy not only increases the pathological complete response (pCR) rate, but fewer patients also develop disease recurrence.

New data reflects in the additional strategies created to further reduce risk and for treatment of high-risk patients. Moving forward, it will be important to recognize how to treat patients with high risk ER-positive breast cancer and what options work best. Whether that be with a CDK4/6 inhibitor, PARP inhibitor, endocrine therapy, or something else, guidelines will change as data comes out.

In an interview with Targeted Oncology^TM, William J. Gradishar, MD, professor of medicine of hematology and oncology, Betsy Bramsen Professor of Breast Oncology, and chief of hematology and oncology in the Department of Medicine at the Feinberg School of Medicine at Northwestern University, discussed the current landscape of caring for patients with advanced breast cancer.

What are the key updates on the management of patients with advanced breast cancer?

Gradishar: What we're doing in breast cancer guidelines is reflecting new data that becomes available. The things that have changed most recently are in the ER-positive breast cancer space. Patients that are at significant risk for recurrence have a couple of potential options. One is based on the monarchE study [NCT03155997] and is the inclusion of CDK4/6 inhibitors, specifically abemaciclib, for patients who either have 4 or more lymph nodes, or 1-3 lymph nodes, and some other features that put them in high risk either a bigger tumor or high Ki-67. In that subset of patients, since the risk is high, abemaciclib in the monarchy trial was shown to further reduce the risk of recurrence.

It's a consideration for those patients. We wouldn't use it in node negative patients or patients that have a generally good prognosis, because you're committing patients based on the trial to 2 years of a CDK4/6 inhibitor, which on its own has some potential side effects. It's for the highest risk patients.

The other thing that's emerged recently is the finding the PARP inhibitors, specifically olaparib, in patients who harbor BRCA mutations may further reduce the risk of recurrence and again, this is a higher risk patient. One of the things that people don't appreciate is although we think of triple negative breast cancer as more commonly having BRCA mutations, which is true, compared to hormone sensitive breast cancer, there are just so many more hormone receptor positive breast cancer patients. The potential number of patients who are candidates to receive olaparib in the high-risk setting is much greater.

One of the things that we'll have to be thinking about going forward is if you have these high-risk ER-positive patients, are we going to be treating them with the CD 4/6 inhibitor? Are we going to be treating them if they harbor a BRCA mutation with olaparib? Or what if they have a BRCA mutation and are ER-positive? Are we going to be giving them both agents in addition, endocrine therapy? Of course, we don't know the answer to that yet, but I think what it highlights is that for these higher risk patients, we now have some options that may further reduce the risk of recurrence, which is a good thing. That's included in the guidelines as an update.

The other area that I think is evolving is the use of checkpoint inhibitors as a treatment for early-stage breast cancer for patients at higher risk. Those are patients where we would typically be giving neoadjuvant therapy and those are patients with triple negative disease, usually with bigger tumors or no positive disease. We learned from the trials with pembrolizumab that giving chemotherapy with the addition of pembrolizumab not only increases the pCR rate, the number of patients without evidence of disease in their breast at the time of surgery, but when you go downstream and follow these patients out, there are fewer of them that will develop a recurrence. It's been validated that giving checkpoint inhibitor therapy with chemotherapy preoperatively does further enhance risk reduction, not only in terms of pCR, but recurrence events.

That also begs some additional questions until we were doing checkpoint inhibitors preoperatively. If a patient with triple negative breast cancer received preoperative therapy, and they had residual disease at the time of surgery, we would consider giving them capecitabine [Xeloda], an oral chemotherapy drug. Now with the checkpoint inhibitors, it begs the question do we give them both? Do we give them both pembrolizumab and capecitabine postoperatively? Or as I mentioned with ER-positive disease, what if these triple negative breast cancer patients happen to have a BRCA mutation? Are you going to give them pembrolizumab postoperatively or are you going to give them capecitabine? Are you going to give them some combination? Are you going to give them olaparib after everything’s done? These are still open questions.

Again, all the new data reflects additional strategies we have for further reducing risk and high-risk patients, and I think that's a good thing. We have PARP inhibitors, we have checkpoint inhibitors, we now have at least 1 CDK4/6 inhibitor that's been shown to reduce risk in that group of patients.

In what ways has the management and care of these patients changed over time?

If you go back a decade, it's changed dramatically. In ER-positive disease, it was endocrine therapy alone, and there was nothing additional we would offer to your positive patients. Now, at least in the high-risk patients, we can add a CDK4/6 inhibitor. Furthermore, if you go back a decade, we were sort of stuck in the idea of 5 years of therapy was appropriate, which may be appropriate for a subset of patients, but we now think of tamoxifen for 10 years is probably better than 5, particularly if you have a somewhat higher risk, and are premenopausal. Rather than an indefinite sort of aromatase inhibitor treatment, we probably for most patients can settle on somewhere around 7-8 years, so we've sort of refined how we think about a year of positive disease.

In the triple negative breast cancer space, it was chemotherapy, chemotherapy, and more chemotherapy. Now we can add some nuance to that. We give a lot of patients preoperative chemotherapy, but now we can add checkpoint inhibitors to it. Postoperatively if you had residual disease, there really wasn't anything we would have done 10 years ago. Now we add at a minimum capecitabine. If they're triple negative, they don't have to be PD-L1 positive, we would consider a checkpoint inhibitor. As well, 10 years ago, PARP inhibitors weren't really approved for anything in breast cancer, and now they're both something we use in metastatic disease, as well as in early-stage disease. The theme of all those comments is that we can refine and tailor our therapy more effectively.

Although it's not really the topic of all the questions in the HER2 space, we have similar advances because we now use dual HER2 targeting for many patients. We also are trying to de-escalate therapy. Because we use preoperative therapy, and so many patients with early stage or 2 positive disease, we find that if they have residual disease, we can offer them a different kind of anti-HER2 therapy postoperatively. We are now doing trials where a patient who has a complete pathologic response at the time of surgery, may need no further chemotherapy and may be appropriate for just anti-HER2 therapy alone.

Our approach is for all patients, whatever sort of silo they sit in, hormone sensitive, triple negative hurt to positive, this is becoming more refined and how we do things. The goal is not only to optimize therapy for the patients at highest risk, which may mean escalation. The flip side is true as well. If we can identify patients who have a lower risk of recurrence, we can de-escalate and take things away so they're not exposed to unnecessary side effects.

What questions are ongoing studies looking to answer in the near future?

With respect to early-stage breast cancer and how we approach things, our prediction of who is going to recur is still not perfect. We've made an effort over time to develop molecular tools, whether you're talking about MammaPrint or the oncotype test, to define patients who may need chemotherapy, and those that can be treated effectively and safely with anti-hormone therapy alone. They're not absolutely perfect.

Similarly, trying to determine who needs extended durations of endocrine therapy. We've had potential tools, the breast cancer index, other things, and that is met with some discordance in the results, so it's not entirely clear. We can always use those tools confidently to determine who can stop therapy or who needs to continue it with respect to endocrine therapy. I think as we go forward, we'll probably be developing better molecular tools to identify a minimal residual disease trying to identify those patients who have subclinical microscopic disease. That may be based on circulating tumor DNA or specific signatures from the primary tumor that we can still identify in the blood. Then we'll have to validate whether or not finding those things and treating them results in a better outcome.

The next phase is probably trying to employ some of those molecular tools in a way that helps us further refine what therapies we would give to patients at high risk, but also the same thing, to de-escalate where patients don't need it. Hopefully, we can do that without having to do these 5000 or 7000 patient trials to figure it out.

What other ongoing research can you highlight, that examine patients with advanced breast cancer?

There's a lot of drugs being developed and the general approach to drug development is inevitably if you show that a given drug has activity in patients with advanced disease, metastatic disease, then we try to push it forward into patients with earlier stage disease. The rationale is twofold. From a business standpoint where most of the patients sit in the early-stage breast cancer population, they want to get those drugs earlier. But from a medical standpoint as a patient and as a physician who takes care of the patients, we want to improve on the therapies that currently exist.

For instance, there's a whole group of drugs in the ER-positive space, referred to as oral SERDS that are being developed, some of which will be approved within the next year. They will initially be approved in metastatic disease, but they're already moving into the adjuvant setting. The goal is to see what their effect would be as an adjuvant therapy, might they be more effective. Similarly, they'll be combined with CDK4/6 inhibitors and everything else. It'll shuffle the deck a little bit, potentially, for ER-positive disease.

In patients with her to positive disease and in patients who still have residual disease after surgery where they got preoperative chemotherapy and HER2 therapy. We're now looking at some of the drugs that were most effective recently in advanced disease, like trastuzumab deruxtecan (Enhertu) and tucatinib (Tukysa), to determine whether or not if you utilize those drugs in patients who have residual disease at surgery, might they further reduce the risk and eliminate many patients who would be destined to get a recurrence.

Those are trials that are ongoing. Then in the triple negative breast cancer space, we are doing a lot of different trials, both with immunotherapy as well as other compounds to determine whether we can enhance or minimize the risk of disease recurrence.