Breast Cancer Treatment Advances Lead to Broadened Scope of Personalized Medicine

Harold J. Burstein, MD, PhD

As a result of many positive trials throughout breast cancer in recent years, the treatment armamentarium has blossomed with CDK4/6 inhibitors, checkpoint inhibitors, and antibody-drug conjugates (ADCs) to name a few, explained Harold J. Burstein, MD, PhD, who added that nuanced treatment decisions are still needed, particularly when it comes to neoadjuvant and adjuvant strategies.

“We are figuring out who with ER [estrogen receptor]–positive disease has high enough risk that they really need abemaciclib [Verzenio]. [Additionally,] where do we draw the boundaries for neoadjuvant triple-negative [disease, when] we begin to add pembrolizumab [Keytruda]? Those kinds of things are very compelling clinical questions that arise every day in the practices,” Burstein said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on breast cancer, which he co-chaired.

“A lot of great stuff is happening, and it’s an exciting time to be in oncology across the board. There’s no question that women have more options and that they are doing better in early- and late-stage breast cancer, which is immensely gratifying. The hope is that that continues,” Burstein added.

In the interview, Burstein, professor of medicine, Harvard Medical School, institute physician, Dana-Farber Cancer Institute, discussed treatment updates across HER2-positive breast cancer, adjuvant advances in ER-positive disease, and the domino effect of immunotherapy in triple-negative breast cancer (TNBC).

OncLive^®: In her presentation on HER2-positive breast cancer, Adrienne G. Waks, MD, of Dana-Farber Cancer Institute, highlighted the results of the DESTINY-Breast03 (NCT03529110) and HER2CLIMB (NCT02614794) trials with fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa). Based on the findings, where are these agents commonly being used in practice?

Burstein: Metastatic HER2-positive breast cancer is one of the great success stories right now in advanced breast cancer. Many highly effective drugs have shown survival benefits in clinical trials, [including the addition of] pertuzumab [(Perjeta) to frontline treatment] in the CLEOPATRA study [NCT00567190], ado-trastuzumab emtansine [T-DM1; Kadcyla] compared with an older regimen of lapatinib [Tykerb] and capecitabine [Xeloda], and trastuzumab [Herceptin] itself originally.

The DESTINY-Breast03 study compared second-line treatment with T-DM1 with trastuzumab deruxtecan and showed that in comparing these two antibody-drug conjugates [ADCs], trastuzumab deruxtecan had a much higher response rate, a longer time to progression, and early data suggesting a survival benefit. That agent has really become a very popular choice in second-line treatment.

The HER2CLIMB study also looked at previously treated patients and compared the combination of trastuzumab and capecitabine with trastuzumab, capecitabine, and an oral tyrosine kinase inhibitor tucatinib. The results showed that adding tucatinib to the regimen also improved the time to progression, the response rate, and survival.

These drugs are both approved now for use in metastatic HER2-positive breast cancer. They are preferred choices for second- or third-line therapy. Most patients will get many lines of treatment for HER2-positive metastatic disease. We don’t really know what the optimal [treatment] sequence is, but for many of us, the data from the DESTINY-Breast03 study with trastuzumab deruxtecan is compelling, and that’s probably a more common second-line regimen now.

Both tucatinib and trastuzumab deruxtecan have central nervous system activity in women with HER2-positive brain metastases. For patients, the most important thing is to know that there are many very good options. For clinical investigators, the important thing to know is survival should be the goal. We’ve had too many studies that have been satisfied by progression-free survival [PFS], but now when you see multiple studies over the years showing you can use better anti-HER2 drugs to achieve survival benefit; that should be the end point we’re looking at.

Dr Waks also spoke about the significance of the KATHERINE (NCT01772472) and the FeDeriCa (NCT03493854) trials with T-DM1 and the fixed-dose combination of pertuzumab and trastuzumab. What did the findings from these trials mean in terms of individualizing treatment for patients with HER2-positive disease?

The KATHERINE study was a very important study. The trial enrolled women who had HER2-positive, earlier-stage breast cancer who received neoadjuvant therapy with a trastuzumab-containing regimen but had residual cancer at the time of surgery. Those patients were randomized to ongoing trastuzumab-based treatment or T-DM1. The investigators showed that switching to T-DM1 substantially lowered the risk of recurrence, and that really is our standard approach these days. We use chemotherapy, trastuzumab, typically paired with pertuzumab for stage II or III breast cancer. If the patient achieves a pathologic complete response, then they get maintenance trastuzumab, pertuzumab [plus chemotherapy], and if they have residual disease, they switch to T-DM1.

That study was sponsored by Genentech/Roche as was the FeDeriCa study, which looked at a fixed dose of the trastuzumab/pertuzumab subcutaneous injection combination and showed the same long-term outcomes as patients who got the intravenous [IV] formulation. For some patients who have access to the subcutaneous packaging of trastuzumab/pertuzumab, that’s a nice option. They can have it administered in the clinic or even, in theory, give it to themselves with a nurse’s or other physician assistant’s guidance at home. That, again, is a reasonably well-tolerated option. For the most part, we’re still doing the IV treatments [at Dana-Farber Cancer Institute]. Patients don’t mind coming in every 3 weeks for the infusions. Occasionally, patients don’t tolerate the combination of trastuzumab and pertuzumab because of diarrhea or other adverse effects [AEs]. Giving the IV [formulation] gives you control over whether you’re giving both drugs or just one drug at a time.

The presentation Philip D. Poorvu, MD, of Dana-Farber Cancer Institute, gave focused on ER-positive, HER2-negative breast cancer. Could you highlight some of the meaningful advances that have been made in the early-stage setting?

A lot of great studies have been going on in ER-positive, HER2-negative early-stage breast cancer. Probably the most important work has been the work that showed that many of these women can avoid chemotherapy. Prospective randomized trials like TAILORx [NCT00310180], RxPONDER [NCT01272037], and the MINDACT study [NCT00433589] have all shown that postmenopausal women who have tumors with low-risk genomic scores can safely avoid chemotherapy because it does not improve their outcomes. There’s controversy over [whether that’s true for] premenopausal women because in several of those studies, there was a benefit for chemotherapy. What we don’t know is how much of that benefit was achieved because the chemotherapy pushed the patient into menopause as opposed to serving a cytotoxic or anticancer direct effect.

At [Dana-Farber Cancer Institute], there are many premenopausal women who do not need chemotherapy, with low-risk genomic scores, and we often use ovarian suppression and endocrine treatment instead of chemotherapy in those patients. We’ve also learned that longer durations can be important. Treating women for out to 7 or 10 years with antiestrogen medications, particularly for node-positive patients, helps lower the risk of recurrence.

Finally, we’ve learned that in younger, premenopausal women ovarian suppression can also help prevent recurrence, and, now with long-term follow-up of 12 years, improve overall survival [OS]. Even though this is the most common kind of breast cancer––ER-positive breast cancer accounts for about 75% of all breast cancers––we’re still learning substantial things about how best to use these hormone manipulations.

Looking at the monarchE trial (NCT03155997), what has abemaciclib (Verzenio) demonstrated in high-risk patients with ER-positive, HER2-negative disease?

The monarchE study was 1 of 3 studies that has looked at adjuvant use of CDK4/6 inhibitors. The monarchE study used abemaciclib. Two other studies, the PALLAS trial [NCT02513394] and the PENELOPE-B trial [NCT01864746] used palbociclib [Ibrance] as the CDK4/6 inhibitor. Those studies have all reported their topline results. The PALLAS and PENELOPE-B studies did not show a major improvement [with palbociclib]. In fact, it showed really no difference in outcome with the use of the CDK4/6 inhibitor, whereas the monarchE did show that adding abemaciclib made a difference in terms of early recurrence risk. Women who took the abemaciclib had a slightly lower risk of recurrence [than those who did not].

It’s important to remember that [monarchE enrolled] a group of patients with very high-risk breast cancer. They either had to have 4 or more positive nodes, or they had to have 1 to 3 positive nodes with additional adverse factors like a tumor greater than 5 cm or high-grade tumor features or a high Ki-67 index of greater than 20%. This is not most patients with breast cancer with screen detected, lower-risk breast cancers. But for those high-risk patients, it does look like abemaciclib might lower the risk of recurrence.

There are a couple of other important things to know. The first is that to date, there’s no OS benefit [with abemaciclib]. Secondly, the data have only 2 to 3 years of follow-up; it’s still very short term, and the patients received 2 years of abemaciclib. What we don’t know is if those curves come apart whether they are going to come back together again with longer follow-up. It is important to continue to monitor this study very carefully and see what the longer-term results hold for such patients.

Finally, the FDA has approved abemaciclib for this purpose, but only in those tumors that have a very high Ki-67 index greater than 20% because in that group, the risk was, at baseline, a little higher, so the numerical benefit of added abemaciclib was a little greater. We’re still figuring out how best to use this drug. It does have AEs, including hair thinning and lower blood counts. The most common concern has been diarrhea, but we are using it in very high-risk patients currently.

All 3 CDK4/6 inhibitors, palbociclib, ribociclib [Kisqali], and abemaciclib are approved for use in the metastatic setting, and each has shown very similar outcomes in terms of PFS and OS benefit. In the metastatic setting, any one of these agents is quite reasonable. Now, only abemaciclib has shown clinical benefit in early-stage setting, so that’s the preferred option there.

Dr Poorvu also spoke about shifting standards in the advanced setting. Could selective estrogen receptor degraders (SERDs) and ADCs come to play a larger role in the treatment of patients with advanced ER-positive disease?

We already use a SERD in ER-positive, advanced breast cancer: fulvestrant [Faslodex]. It’s an injectable SERD, and there’s a lot of interest right now in orally available SERDs and other ways of targeting the ER. There must be 5 or 6 companies that have oral SERDs in development. We saw the first report last year from the EMERALD study [NCT03778931], looking at an oral SERD vs standard of care. The oral SERD looked to be about the same [as the standard of care].

Maybe in some small groups, there was clinical benefit.

One of the challenges of these studies is that the control arm in several of them was what they called standard of care, but in fact, many of these patients were getting drugs they already had before. [For example,] they previously had an aromatase inhibitor [AI], and they were offered an AI again, or they previously had fulvestrant and they were given fulvestrant again. People are really interested to see how the oral SERD stacks up against, say fulvestrant in patients who have not already had fulvestrant. We’re still looking for a direct comparison there to see what the benefits could be. At the same time, people appreciate that an orally available medicine is a lot easier than having to come in once a month for an intramuscular injection. There is excitement about this class of drugs overall.

We use ADCs in different settings in advanced breast cancer. We use sacituzumab govitecan-hziy [Trodelvy] in TNBC and trastuzumab deruxtecan in HER2-positive breast cancer. There have also been press reports from the companies that make both of those drugs that in comparing their product against existing standard-of-care chemotherapies that their drugs did better. Both Daiichi Sankyo and AstraZeneca, which manufacture trastuzumab deruxtecan issued results suggesting that that agent outperformed single-agent chemotherapy in second- and third-line treatment of patients with ER-positive, HER2-low breast cancer; HER2 1+ or 2+. Similarly, Gilead reported results that sacituzumab govitecan outperformed standard chemotherapy in the second and third line of ER-positive, HER2-negative cancers. We suspect that these ADCs, which were developed as very targeted drugs in special populations are going to start to bridge some of those boundaries and be active in other kinds of breast cancer as well.

The last presentation, given by Sara M. Tolaney, MD, MPH, of Dana-Farber Institute, centered around treatment in TNBC. How has treatment intensification been shown to improve outcomes?

Triple-negative disease has long been looking for some better treatment options and we’re seeing nice progress there. One thing that’s become very important is immunotherapy. In metastatic triple-negative cancer, if the tumor is PD-L1 positive, we are now routinely adding pembrolizumab [Keytruda], the PD-1 inhibitor to standard chemotherapy for first-line treatment, and that’s been shown to be beneficial.

In early-stage breast cancer in the neoadjuvant setting, it’s also been shown in the KEYNOTE-522 study [NCT03036488] from Merck that adding pembrolizumab to standard chemotherapy consisting of paclitaxel, carboplatin, doxorubicin, and cyclophosphamide improves the rate of complete pathologic response, and, now with longer follow-up, seems to be showing benefit in terms of PFS and even OS. There are of course AEs to these therapies; oncologists know these very well, but in addition to inflammation like pneumonitis and colitis, there are risks of endocrinopathies, including hypothyroidism, hypoadrenalism, and even hypopituitarism. Those are things people need to be familiar with, and because we’re talking about early-stage breast cancer, which many women will be cured of, the long-term risks of those [toxicities] are going to be important to characterize. But clearly, immunotherapy has found a home in TNBC and that is good news.

Dr Tolaney also mentioned sacituzumab govitecan, which is now a very standard second- or third-line regimen for advanced TNBC and clearly has clinical activity as well. Those are very positive developments.

The other thing that’s going to change [treatment for] some subsets of TNBC are the PARP inhibitors. Women who have hereditary BRCA1 mutations and sometimes BRCA2 or PALB2 [mutations] are more likely to have TNBC, and studies in the metastatic setting, and, now, in the early-stage setting, have shown that adding a PARP inhibitor such as olaparib [Lynparza] improves outcomes as well. That that does two things: it creates yet another therapeutic option for the small subset of patients who have TNBC and BRCA1/2 mutations and it provides justification for more widespread genetic testing in women with early-stage breast cancer than in the past.

What would you like to emphasize about the treatment landscape to community oncologists?

Increasingly, we are using novel and new classes of drugs to treat [patients with] advanced disease, [including] ADCs, immunotherapy, and PARP inhibitors. In the ER-positive space CDK4/6 inhibitors are widely established now, and SERDs and medicines like them are coming along. We will increasingly be leaning on genomic sequencing to identify mutations that might lend themselves to unusual, targeted therapies. We will be looking at more genetic testing to see whether women should get PARP inhibitors. All these are very positive developments for patients.