Expert Analysis From SABCS 2012: An Interview With Edith Perez, MD

Edith Perez, MD

At the 2012 San Antonio Breast Cancer Symposium (SABCS) we had the privilege of sitting down with Edith Perez, MD, whose breast cancer research has included groundbreaking work with both trastuzumab and T-DM1. Perez is the deputy director of the Mayo Clinic Cancer Center and practices at Mayo Clinic in Jacksonville, Florida. She is also Director of the Breast Cancer Translational Genomics Program and Serene M. and Frances C. Durling Professor of Medicine at the Mayo Medical School. We spoke with her about key research presented at SABCS, ongoing developments in breast cancer treatment, and the current focal areas of her research.

Oncology & Biotech News: You were one of the authors of a phase III study presented at SABCS that examined eribulin mesylate in advanced breast cancer.¹ What were the study results?

Dr Perez: This was a very well-conducted global trial evaluating whether eribulin was better than capecitabine for patients with refractory metastatic breast cancer. But the researchers did more than that. They actually enrolled patients who were eligible to receive chemotherapy in the first-, second-, or third-line setting for metastatic disease.

The results demonstrated that eribulin was not better than capecitabine. Specifically, the data show that the two drugs appeared to be fairly similar in terms of efficacy, where efficacy was defined as progression-free and overall survival. There was a little bit of a trend, actually, for improvement of eribulin over capecitabine but it did not reach statistical significance.

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Dr. Edith Perez on the Phase III Eribulin Versus Capecitabine Study

Another interesting aspect of this study was that investigators conducted a subset exploratory analysis and there were two subgroups of patients who appeared to potentially benefit more from eribulin compared with capecitabine. They were patients with triple-negative breast cancer and patients with HER2-negative breast cancer.

So, the take-home messages include that there are alternatives for patient management: Either eribulin or capecitabine can be used in the first-, second-, or third-line setting. Additionally, the results provide support for further studies, such as evaluating eribulin in patients with HER2- negative or triple-negative breast cancer.

Please discuss the ongoing research you presented at SABCS that involves identifying genomic predictors of treatment outcomes in the phase III N9831 trial.²

We’re very enthusiastic about the results of our study evaluating the potential role of gene expression profiles with the outcome of patients who participated in our N9831 adjuvant trastuzumab trial. As many people know, we and others conducted the original clinical trials that led to the approval of trastuzumab in the adjuvant setting here in the United States and in many parts of the world. An important fact is that although the results have been impressive, not all patients are cured, even if they receive the best combination therapy with trastuzumab and chemotherapy. Thus, we have focused efforts to interrogate the tissue and blood specimens that we collected from the patients who consented, so that we could better understand the biology and identify factors that may help us better predict responsiveness to therapy.

At this meeting we are reporting, for the first time, gene association findings that correlate with outcomes for patients who enrolled in this translational clinical trial. We found, after many years of work and team collaboration, that at a very high level of statistical significance, with a P value of less than 0.001, expression of 32 genes correlated with patient outcome. Specifically, 27 of those genes were associated with good outcomes and five correlated with poorer outcomes in patients treated with chemotherapy and trastuzumab.

So the logical next questions are: “What are you doing with this information next? Are you ready to recommend the physicians order evaluations of those genes for decisions on therapy?” My answer to that is that these results give us the path for validation to eventually help develop a laboratory test that could be used for clinical practice. I can now share that the plans for collaboration are going well, as we already have agreement from several investigators who conducted adjuvant trastuzumab trials or neoadjuvant trials to share their specimens with us. This is necessary to validate our findings, and I offer my thanks on behalf of science and our patients. I expect we should have something in the next few months.

While on the subject of trastuzumab, what has research presented at SABCS and elsewhere told us about the optimal duration of adjuvant trastuzumab in HER2-positive, early-stage breast cancer?

One of the questions that has existed since 2005, when we first reported the data of trastuzumab improving upon chemotherapy in terms of diseasefree survival for patients with HER2-positive breast cancer, was whether our decision to evaluate trastuzumab for 1 year was the correct decision. Many people said, “Well, how about if we give it for 2 years, how about if we give it for 3 weeks, how about if we give it for 9 weeks, or for 6 months.” So, over the last 4 months or so when we heard the data from the PHARE trial [6 months vs 1 year of trastuzumab] and the HERA trial [1 year vs 2 years of trastuzumab],³ we have reached the conclusion that the current standard of 1 year of trastuzumab is indeed the appropriate duration of adjuvant therapy with this targeted agent.

What are the next steps with trastuzumab in terms of combination therapy?

Research added to education, so that the results of our work can translate into better lives for our patients. We recently reported our data demonstrating that the optimal way to incorporate trastuzumab was concurrent (instead of sequential) with the taxane portion of the treatment. This is something that physicians can now use for standard practice.

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Dr. Edith Perez on the Adjuvant Treatment of Breast Cancer

But, beyond that, what is being done now in the adjuvant setting is to determine whether we should add another type of anti-HER2 therapy to trastuzumab. Accrual has been completed for the ALTTO study [http://goo.gl/53cVT], in which we are evaluating the addition of lapatinib. We expect data from this global study within the next year-and-a-half. The other agent being evaluated in combination with trastuzumab is pertuzumab, in the APHINITY trial. An idea that we are supportive of development is the evaluation of a yet different anti-HER2 agent: T-DM1. So, the future is bright. We are incorporating biology and utilizing the latest molecular tools for interrogation of tissue/ blood specimens consistent with the collaboration of the San Antonio Breast Cancer Symposium with the AACR. These newer studies are being conducted with appropriate collection of biological specimens to improve patient care.

The phase III BEATRICE trial presented at SABCS evaluated adjuvant bevacizumab in triple-negative breast cancer.⁴ Can you discuss the study as well as other current research in treating triple-negative disease?

Breast cancer is a heterogeneous and complex disease. It affects too many people worldwide. But over the last few years we’ve really begun to better understand the differences between the different types. We still have the major subtypes: estrogen receptor—positive, HER2-positive, and triple negative disease. However, it is recognized that there may be various subtypes within each one of these major subsets, including the triple-negative category. Thus, I think it’s appropriate to develop clinical trials that enroll patients with “so-called” triple-negative breast cancer to evaluate potential new avenues for treatment. All of these trials, in my opinion, should be accompanied by collection of tumor and blood specimens so that we can better understand the biology of the disease.

The presentation [of the data] from the BEATRICE trial here at San Antonio was quite sobering and important. Investigators evaluated whether adding bevacizumab to chemotherapy could improve outcomes in the adjuvant setting for patients with triple-negative breast cancer. As a disappointment to many of us, the BEATRICE study demonstrated that bevacizumab did not add to chemotherapy. So this is one of the situations in which there was a good hypothesis, a well-conducted study has now been reported, and we can move on.

There is a lot of other work being done in the setting of triple-negative breast cancer. For example, our group [at Mayo Clinic] led by Alvaro Moreno-Aspitia, MD, reported preliminary data at this meeting of a phase II study evaluating a new agent called brostallicin in combination with cisplatin for patients with metastatic triple-negative breast cancer.⁵ We’re very encouraged by these data and plan to present follow-up information at the ASCO annual meeting. In addition to brostallicin, which is a DNA small-groove inhibitor, there are some preclinical data that support trials evaluating PI3 kinase inhibitors, MEK inhibitors, and MET inhibitors. So we’ll have to see what the research shows.

A study presented at this symposium examined breast cancer genome sequencing data and determined that HER2 mutations could be targeted with cancer drugs, even in HER2-negative patients.⁶ Where are we with HER2 testing in breast cancer?

HER2 testing is a very important example of understanding the biology of breast cancer, finding a target, developing a diagnostic test, figuring out what test should be done, and how it should be interpreted in the context of practice all over the world. So I think interrogating the genome is going to be complex. Research in preclinical models and translational clinical trials, as we and others reported at this meeting, will help us in this path.

The BOLERO-2 everolimus trial was a key study presented at SABCS last year. Where are we now with the BOLERO trials?

The evaluation of mTOR inhibitors such as everolimus has been done in a programmatic fashion. The company [Novartis] and the investigators evaluated everolimus in the setting of hormone receptor—positive breast cancer, which was the BOLERO-2 trial. Additionally, there are two trials in the setting of HER2-positive disease: BOLERO-1 [everolimus in combination with trastuzumab and paclitaxel; http://goo.gl/IeGCA] in the first-line setting and BOLERO-3 [everolimus in combination with trastuzumab and vinorelbine; http://goo.gl/pCqWz] in the refractory setting.

We heard the results of BOLERO-2 last year [at SABCS] and the data were published in the The New England Journal of Medicine. The follow-up data presented at this SABCS clearly showed that adding everolimus to exemestane in the refractory hormone receptor—positive breast cancer setting led to a significant improvement in progressionfree survival.⁷ We need to wait longer to see if there will be a difference in overall survival, but at least a difference in progression-free survival was of the magnitude that this therapy is to be considered as one of our standards of care.

Related to the other two BOLERO studies evaluating the addition of everolimus to trastuzumab and chemotherapy in either the first-line or refractory setting, I think at least some data should be available this year.

The antibody-drug conjugate T-DM1 has been a big success story in breast cancer this year. What are your thoughts on this new treatment?

T-DM1 is an important new antibody-drug conjugate agent. It combines trastuzumab with chemotherapy, with fairly impressive results reported to date, and more awaited. We’ve been studying this agent for several years, so I’m very happy that many of our patients have had access to this drug as we have been conducting clinical trials at Mayo Clinic. The results that we heard a few months ago for the EMILIA trial, which have been published in The New England Journal of Medicine (http://goo.gl/IeMmh), clearly demonstrate that T-DM1 is better than [the combination of] capecitabine and lapatinib. That was really practice-changing. In the near future, certainly when the drug becomes available via the FDA and other regulatory agencies around the world, more patients will have access to this important agent.

Having the idea of an antibody-drug conjugate was really very good—how can we best combine a targeted anti-HER2 agent, such as trastuzumab, with chemotherapy in a way in which we can optimize efficacy and minimize toxicity? And that’s really what T-DM1 does.

Earlier this year, you published a study in Cancer Research that examined fusion transcripts, a new class of molecular mutations in breast cancer tissue.⁸ Please discuss your research.

We are very interested in implementing strategies that help patients—that’s really the bottom line of our research. The way to do this is through education and conducting clinical trials, and basic research. Our team at Mayo conducts collaborative research to interrogate the genome via nextgeneration gene sequencing, and then develops and applies bioinformatic algorithms to understand what gene profiles may really be telling us. Well, we have recently identified some fusion transcripts that actually align with the three major subtypes of breast cancer: ER-positive, HER2-positive, and triple-negative. This could be a seminal finding.

We think that the fusion transcripts may be very relevant to the development and behavior of breast cancer, including sensitivity to therapy. This is very innovative work and I’m very happy that we’re going to continue our research in this area to corroborate our findings in a larger series of specimens.

What are some other current focal areas of your research?

I continue to be very interested in science, patients, and new strategies for management. So I’ve been really involved with T-DM1 over the last few years. I’m very involved with the MARIANNE trial [T-DM1 plus pertuzumab vs trastuzumab plus a taxane; http://goo.gl/qvagN], which is the first-line metastatic trial, and we anticipate that data will be reported in the next year-and-a-half. This could be a practice-changing study.

I’m also involved with the evaluation of other agents, especially in my role as not only a clinician investigator, but also helping as chair or participant in independent review committees of some major trials. We are looking at a trial with fibroblast growth factor inhibitor, FGF-1. We’re also interested in HDAC inhibitors, and there are a couple of agents currently being evaluated—entinostat and another agent called panobinostat. I’ve also developed some interest lately in the androgen receptor as a target. So we’re consulting with some scientists offering advice related to the development of clinical strategies looking at that pathway.

And last but potentially not the least important, I think there’s still a role for improvement in chemotherapy for patients with advanced breast cancer. So we’re involved in a very innovative trial evaluating a new compound, NKTR-102, which is a pegylated irinotecan compound that has a better pharmacokinetic profile and tolerability than irinotecan in patients with metastatic breast cancer. So I have the honor to be the co-lead globally of a phase III trial called BEACON [http://goo.gl/4VdgN], in which we’re enrolling patients with refractory metastatic breast cancer who were pretreated with anthracyclines, taxanes, and capecitabine. The randomization is to this novel compound versus standard of care. So we will see what the trial shows.

References

1. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Cancer Res. 2012;72(24)(suppl 3): Abstract S6-6.
2. Perez EA, Eckel-Passow JE, Ballman KV, et al. Predictive genomic markers to chemotherapy and adjuvant trastuzumab via whole genome expression DASL profiling in the N9831 adjuvant study. Cancer Res. 2012;72(24) (suppl 3): Abstract PD10-04.
3. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Cancer Res. 2012;72(24)(suppl 3): Abstract S5-2.
4. Cameron D, Brown J, Dent R, et al. Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Cancer Res. 2012;72(24)(suppl 3): Abstract S6-5.
5. Moreno-Aspitia A, Rowland Jr KM, Allred JB, et al. N0937 (Alliance): Preliminary results of a phase II clinical trial of cisplatin and the novel agent brostallicin in patients with metastatic triple negative breast cancer (mTNBC). Cancer Res. 2012;72(24)(suppl 3): P1-12-06.
6. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancers. Cancer Res. 2012;72(24)(suppl 3): Abstract S5-6.
7. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer. Cancer Res. 2012;72(24)(suppl 3): Abstract P6-04-02.
8. Asmann YW, Necela BM, Kalari KR, et al. Detection of redundant fusion transcripts as biomarkers or disease-specific therapeutic targets in breast cancer. Cancer Res. 2012;72(8):1921-1928.