Jury Still Out on Anthracyclines in HER2+ Breast Cancer

Kathy D. Miller, MD: Hi. I'm Kathy Miller, professor of medicine and co-director of the Simon Cancer Center Breast Cancer Program at the Indiana University School of Medicine in Indianapolis.

Welcome to Medscape Oncology Insights and the 2015 San Antonio Breast Cancer Symposium. The meeting is just underway. As has been the case in the last couple of years, HER2-positive disease is a major focus of our discussions and a major focus of the work at this meeting.

Joining me to put these studies into perspective is Dr Sara Tolaney, senior physician and associate director of clinical research in the Susan Smith Center at the Dana-Farber Cancer Institute in Boston. Welcome, Sara.

Sara Tolaney, MD, MPH: Thank you.

10-Year Results: Still No Definitive Answer on Anthracyclines

Dr Miller: One of the areas of controversy for the last 10 years is whether anthracyclines have a role in the treatment of patients with HER2-positive disease. That controversy was first brought to the forefront by the first results of the BCIRG 006 study,^[1] which used a non-anthracycline-containing regimen compared with an anthracycline-trastuzumab regimen. We have the 10-year results at this meeting.^[2] Do those 10-year results resolve the controversy?

Dr Tolaney: I think, unfortunately, they do not. As you know, the BCIRG 006 study randomly assigned patients who had HER2-positive disease to get a taxane, platinum, and trastuzumab, and compared it with a combination of the anthracycline doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), docetaxel (Taxotere), plus trastuzumab (Herceptin) (ACTH); it found that there was no overall significant difference between these arms. There was a slight trend towards a benefit in the anthracycline arm. I do still tend to use anthracycline-based therapy in patients who don't have underlying cardiac risk factors. The young patient who comes in who has an HER2-positive cancer, I am still giving them, you know, the ACTH-based regimen.

Dr Miller: I have to ask you your definition of "young." As I get older, I'm not so happy with some of the definitions these days. When you think about a young patient for whom you would lean towards giving an anthracycline regimen, where is your threshold where you start to question that?

Dr Tolaney: Most of the studies that have looked at risk factors for trastuzumab-based cardiotoxicity have shown that a patient over the age of 60 years who has some other cardiac risk factors such as hypertension and borderline ejection fraction is at a higher risk of developing trastuzumab-based toxicity. Those are the patients I tend to have more concerns about exposing to an anthracycline and trastuzumab. I do think a non-anthracycline-based regimen in that population is still very reasonable.

Dr Miller: The risk factors that referring physicians ask me about are hypertension, diabetes, and previous myocardial infarction (MI) but with a normal ejection fraction. Do any of those come into play in your clinical decision-making?

Dr Tolaney: All of those factors need to be factored in. We recently did a study trying to evaluate which patients are at highest risk for trastuzumab-based cardiotoxicity^[3] and found that it was age over 60 years and having two cardiac risk factors—whether that's hypertension, prior MI, or borderline ejection fraction—that seemed to be most predictive. All of those things should be taken into account.

Dr Miller: That actually makes it easy because many of our listeners struggle with this question on a regular basis. They can listen to folks maybe from Dana-Farber and some of the East Coast cancer centers and hear that anthracyclines still have a role. They may also hear folks from the West Coast saying, "Statistically, there's no difference, but there is a difference in toxicity. Maybe anthracyclines should not have a role." I like your strategy of individualizing the treatment, trying to balance risk for disease and risk for toxicity.

Dr Tolaney: Again, both are very reasonable regimens, but given that there's a slight trend towards benefit in the anthracycline arm, I do tend to use anthracyclines in patients who don't have significant risk of developing cardiac toxicity.

Benefit of Neratinib Must Outweigh Toxicities

Dr Miller: There is another adjuvant study^[4,5] being updated at this meeting, a study looking at extending the duration of HER2-targeted treatment by randomly assigning patients who have finished a year of trastuzumab to receive an additional year of neratinib or not. This study, which we first saw at the American Society of Clinical Oncology (ASCO) 2015 annual meeting,^[5] showed a small benefit from neratinib; I think that was a surprise to many of us, given that an additional year of trastuzumab in the HERA trial^[6] was not helpful. You've had some personal experience with neratinib. Could you give our listeners a bit of an update about that agent, its mechanism of action, and some of its toxicities?

Dr Tolaney: Neratinib is an oral tyrosine kinase inhibitor that's a pan-HER2 inhibitor. It's a very potent inhibitor of HER2, and I think it has very great activity. But it does have significant toxicity, and one of the biggest toxicities is diarrhea. Almost 40% of patients develop grade 3 or 4 diarrhea with this agent, so it's not insignificant, and it does result in several dose reductions.

When you're looking at giving a patient, someone who's completed a year of trastuzumab (and who may have received chemotherapy prior to trastuzumab) an additional HER2 therapy—one that is associated with significant toxicities—it's a lot. I think you would need to see a very large difference in outcome to make it worthwhile, and what we're seeing is a small one. One has to be cautious about exposing patients to long-duration therapies that have significant toxicities. Unless they have very high-risk HER2-positive disease, it's hard for me to get too excited about it.

Dr Miller: Neratinib is not an agent that's immediately available, but we expect that the US Food and Drug Administration (FDA) may be reviewing these data. One of the challenges we may have, if this agent does get FDA approval, is putting it into context of other therapies because adjuvant therapy for HER2-positive disease is shifting as we speak. Those patients who got neoadjuvant therapy may now get pertuzumab. We may hear the results of the APHINITY trial^[7] in the not too distant future that may change adjuvant therapy. Will the results of the neratinib trial still be relevant to those patients who might have already gotten dual HER2 blockade as part of their early therapy?

Dr Tolaney: That's an excellent question and certainly one we can't really answer, but I think it does make one question adding an agent in a setting of patients who may have had prior pertuzumab. If the outcomes from APHINITY are positive, and adjuvant pertuzumab does become a standard, it again makes me question whether or not I would want to use neratinib in that population of patients because the ExteNET study was done in patients who had not had any prior pertuzumab. Preoperative pertuzumab was not available at that time, and so the landscape is going to change.

TH3RESA Shows Benefit in Third-Line Metastatic Setting

Dr Miller: The other area where the landscape has changed is in our patients with metastatic disease. While we've made really substantial improvements in treatment of early-stage HER2-positive disease, there are still those patients who are stage IV at presentation. Our early-stage therapy isn't perfect. It doesn't work for everyone. Probably the biggest news in the metastatic world was T-DM1, initially with the results of the EMILIA trial,^[8] but at this meeting we see the overall survival results of the TH3RESA trial.^[9] Remind our listeners about the population and the design of the TH3RESA study.

Dr Tolaney: The TH3RESA trial was a trial for women who have metastatic HER2-positive breast cancer that has progressed on prior trastuzumab-based regimens, and they were randomly assigned to receive T-DM1 or treatment of physicians' choice. This study had not only a benefit in terms of progression-free survival but also in overall survival.

This really reinforces what we've learned about T-DM1 over the years. We know from the EMILIA study that when T-DM1 was compared to with capecitabine and lapatinib, it was superior both in terms of progression-free and overall survival. That was in predominantly the second-line setting, and now the TH3RESA study is predominantly in the third-line setting and beyond. So this agent is showing activity in the second-line and beyond and for all patients with HER2-positive disease, which is pretty impressive.

Dr Miller: The one outlier in those results in the metastatic setting is the MARIANNE trial. You know, we talked fairly extensively about the MARIANNE trial^[10] at the 2015 ASCO meeting when we first saw the details of those results. The MARIANNE trial compared the standard at the time of a taxane and trastuzumab vs either T-DM1 or T-DM1 plus pertuzumab. Many in the community, judging by the positive results of T-DM1 in more refractory patients, expected TDM-1 to be superior. But it wasn't.

Dr Tolaney: I think it was surprising to all of us. We had phase 2 data that had compared docetaxel and trastuzumab vs T-DM1 in the first-line setting,^[11] which made us really excited about T-DM1 potentially being superior to a taxane and trastuzumab. Then the MARIANNE study came out and really showed us that there really isn't a significant difference and that adding pertuzumab to T-DM1 did not seem to change things. I think both of those findings were quite surprising, but I think they really didn't change the standard of care. In the first-line setting, we still believe that a taxane, trastuzumab, and pertuzumab is the right therapy on the basis of CLEOPATRA^[12]; and in the second-line setting, T-DM1 becomes a very reasonable option but isn't a reasonable option at this time in the first-line setting.

Dr Miller: A couple of other practical questions, as we wrap up here, that come to me from a lot of our listeners: In the metastatic setting, how often do you evaluate cardiac function in patients who are getting trastuzumab or pertuzumab or T-DM1?

Dr Tolaney: Not very often. You have to weigh benefits and risks, which are very different in the metastatic setting compared with the adjuvant setting. Obviously in the adjuvant setting I'm monitoring cardiac toxicity every 3 months in patients getting trastuzumab-based chemotherapy. But in the metastatic setting, our threshold to omit anti-HER2 therapy is very different. Unless a patient is developing symptoms suggestive of cardiac toxicity, I'm not too eager to go looking. I don't routinely get cardiac imaging in those patients.

Dr Miller: Thank you, Sara. There will continue to be a lot of other developments in novel HER2 treatments, really beginning to refine which of our HER2-positive patients need what therapy.

Dr Tolaney: Exactly. There are many novel drugs out there. It'll be exciting to see how it all evolves.

Dr Miller: Thank you for joining me, Sara. This is Dr Kathy Miller reporting from San Antonio.