Collaboration Across Disciplines Driving Progress in Breast Cancer: A Conversation With Debu Tripathy, MD

Debu Tripathy, MD

Debu Tripathy, MD, professor of medicine and co-leader of the Women’s Cancer Program at the University of Southern California Norris Comprehensive Cancer Center, was one of four co-chairs of the 2012 Miami Breast Cancer Conference.

Tripathy described the conference as especially valuable because of the multidisciplinary perspective that infused this year’s program. He sat down with Oncology & Biotech News to speak about how collaboration among disciplines has led to intriguing new findings in breast cancer research that are driving progress in his field.

OBTN: As a long-time attendee of other major breast cancer meetings, and now one of the co-chairs of the Miami Breast Cancer Conference, can you discuss the features that set this meeting apart from other breast cancer conferences?

Dr Tripathy: The Miami Breast Cancer Conference has always had a unique niche among the conferences about breast cancer that occur globally each year. It started off as an opportunity for surgeons to learn more about biology and other disciplines, but over the years the Miami Breast Cancer Conference has become a multidisciplinary conference. Most importantly, it creates a bridge between the basic sciences and all the clinical disciplines. Not only is there an interaction between experts in the field of radiology, pathology, and surgical/ medical/radiation oncology, but basic scientists provide a biological perspective that is becoming increasingly important in the management of breast cancer. When you think about where we are today, a breast cancer physician has to be a biologist, a statistician, a psychologist, and a clinician. So understanding the molecular events that drive the development of breast cancer will become more important for physicians in formulating diagnostic and therapeutic plans and effectively communicating these to patients.

How does the medical oncologist decide who needs chemotherapy for a low-risk lesion? How do we combat the problem of drug resistance? How do we make sure that our surgical margins are truly negative and are going to result in the lowest local recurrence? How do we decide what type of radiation field to use that maximizes the benefit and minimizes the toxicity? The key to finding these answers lies both in the discoveries of basic science as well as in the level of evidence that is being built from clinical trials. This is precisely what this conference brings together for the clinicians: a perspective that spans the biology, the statistics, the clinical evidence, and the behavioral and psychological issues that our patients are dealing with in making decisions.

How does this meeting address these issues in a way that’s meaningful for each specialist?

We have speakers and audience members from every specialty, including medical, surgical, radiation oncology, medical genetics, behavioral psychology, radiology, pathology, biostatistics, and, of course, the basic sciences. I’m a medical oncologist by training, but one of the things that drew me to the field of breast cancer was its incredible intellectual richness—from the basic sciences to all the different disciplines—and a way to take that and apply it to the patients for whom we care. In the area of medical oncology, we are increasingly dependent on our basic science colleagues to point us in the direction of how new therapies work and how to choose the appropriate patients for specific therapies. We also have to work closely with our pathologists to understand the biomarker landscape of the tumors so we can choose the best treatment, and with our surgical colleagues so that they can communicate ahead of time to the patient what systemic treatments might be needed after surgery.

I find that, as a medical oncologist, this conference allows me to interact with my colleagues in a very real-life way—the way that I work in my own practice, where I am in constant touch with my colleagues regarding input that I might need from the different specialties, and then, of course, integrating this all into an effective decision-making exercise.

What important highlights are being presented at this year’s Miami Breast Cancer Conference that have the potential to affect treatment and treatment decisions?

In adjuvant therapy, the use of molecular profiling to make decisions regarding the benefit of chemotherapy when added to hormonal therapy for hormone receptor-positive and HER2-negative disease is an ongoing story. We now have established reasonably well that, for node-negative breast cancer, we can identify subgroups of patients that are more likely to benefit from chemotherapy. This has always been an important area, because the benefits overall in node-negative cancer are very small. We’ve always wondered whether there may be a subgroup of patients that’s really deriving the lion’s share of the benefit. In fact, we now know this is the case.

An area in which we are less certain about the role of gene profiling is node-positive breast cancer. There may be a group of patients who are at higher risk for recurrence but will still get most of their benefit from hormonal therapy. Can we avoid chemotherapy in these patients without affecting their outcome adversely? The answer appears to be “yes” based on a few small, retrospective studies. There are patients who, for their own value systems, would only want to take chemotherapy if it was going to impart a very significant difference in their likelihood of recurrence or dying of breast cancer. For those patients, I believe molecular profiling may have a role. It has to be discussed on a case-by-case basis. There is now a prospective trial ongoing called the RESPONDER RX study for patients with one to three positive nodes whose tumors are hormone-receptor positive and HER2-negative. These patients, if they have a score under 25 as measured by the 21-gene recurrence score, are randomized to hormonal therapy alone versus chemotherapy followed by hormonal therapy, whereas those with a high-risk score (≥25) automatically get chemotherapy.

These are the kinds of studies that are clinically important in gaining a higher level of confidence and refining the way we use these assays for future patients. What I see coming in the future are better molecular prognostic tools that tell us what drug to use or whether someone may harbor the likelihood of becoming resistant to a particular therapy—for example with HER2-directed therapy—and whether we might use additional agents for certain cases.

What triggers resistance to these drugs, and are there treatments or new drugs that can reverse and/or overcome this process?

Over the last decade or so, we’ve gained some insight into at least some of the mechanisms of resistance to hormonal therapy, and they tend to deal with activation of growth-factor receptor pathways. These pathways are highly complex and interacting. They involve receptors such as HER2 and the epidermal growth factor receptor, and they also involve downstream mediators such as PI3 kinase and mTOR. mTOR is a particularly important protein because it’s at the crossroads of numerous cellular signals that involve both hypoxia signaling and growth-factor receptor signaling, as well as cell metabolism. In a sense, it’s a protein that drives metabolism and the synthesis of proteins that are involved in the cell cycle. So, it’s a critical mediator, and it’s been known that when you inhibit this protein, you can induce a sensitivity to hormonal therapies or reverse resistance. As mTOR inhibitors have become available as an established treatment for renal cell cancer because of the mTOR-driven hypoxia pathways involved in this malignancy, they have also been tested in patients who are on hormonal therapy to prevent the development of resistance.

One important study called the BOLERO-2 study enrolled postmenopausal patients who were receiving second-line hormonal therapy after progression on a nonsteroidal aromatase inhibitor. They were randomized to exemestane (which is a standard treatment for such patients) with placebo, or to exemestane with everolimus, an mTOR inhibitor. This study showed a dramatic improvement in progression-free survival, a doubling of the median time to progression. These effects were seen in all subgroups analyzed, so this was a rather profound effect. Very rarely in metastatic breast cancer have we seen an impact this big with the use of a new therapy.

There are some side effects with mTOR inhibitors. They can cause fatigue, hyperglycemia, and stomatitis. Fortunately, highgrade toxicities are not as frequent, but they are an important consideration in using these drugs. The survival data on this study have not yet been matured. There have not been enough events for the formal survival analysis, but, based on the data so far, this drug is very likely to be approved by the FDA. This will be reviewed later this year and will probably impact the standard of care for second-line hormonal therapy.

The challenges ahead are still going to be how to identify the optimal patients for this treatment, how to identify patients who may be at risk for the side effects, and how to manage the side effects.

The general problem of drug resistance applies in many other settings, particularly in the area of HER2neu-positive breast cancer, where, of course, the monoclonal HER2 antibody trastuzumab has been a very important component of treatment—both in the adjuvant setting, where it cuts the recurrence risk by anywhere from onehalf to one-third, and in the metastatic setting, where it clearly improves survival when added to chemotherapy. This drug has really changed the face of HER2-positive breast cancer. It used to be an adverse prognostic sign. Patients with HER2-positive disease lived a shorter life and had more aggressive disease. The advent of HER2 targeting has made this type of cancer more survivable. However, in the metastatic setting, as with hormonal therapy, resistance develops in most patients. The mechanisms of this are not fully understood.

Debu Tripathy, MD speaking at the Miami Breast Cancer Conference.

At the time that trastuzumab was developed, a second antibody, pertuzumab, was studied alongside it. This antibody works a little bit differently than trastuzumab. It inhibits the dimerization of the HER2 receptor with its partners, and as a single agent does not have that much activity. However, in combination with trastuzumab, in many of the preclinical models, there was some promise that this may be more effective. The CLEOPATRA study was conducted in patients with HER2-positive metastatic breast cancer getting first-line therapy. Patients were treated with the standard regimen of trastuzumab and docetaxel as the control arm, compared with the same regimen with the addition of pertuzumab. This study also showed a pretty significant improvement in progression-free survival, a hazard ratio of roughly 0.6. That means about a 40% extension in progression-free survival. This drug is likely to also be approved by the FDA when it is presented later this year. This is another advance in the treatment of patients with HER2-positive breast cancer, and spells yet another sequential and slow expansion of the survival time of this group of patients.

As with any new therapy, it also poses challenges. There are some added toxicities, but they are modest. For example, there is a little more diarrhea with the use of pertuzumab, but fortunately, there does not appear to be an increase in the risk of cardiac toxicity. Another issue that we all have to be conscious of is the cost of these therapies. These are significant, and the burden is increasingly placed on patients. So, as time goes on, not only are we going to have to sequentially improve outcome, we’re going to have to do a better job of identifying who is really going to respond to these therapies.

Over the past few decades, our understanding of the association between cholesterol and hypertension has led to a significant decrease in the number of people dying of heart attacks, and of overall cardiovascular mortality. That’s largely been due to the development of new cholesterollowering agents and a greater push for prevention. Can the same lessons be applied in breast cancer?

We’re starting to understand at a biological level that estrogen is an important driver of breast cancer. Very elegant presentations at today’s session discussed two general pathways of cancer development: one for hormone receptor-positive cancers and the other for the more aggressive triple-negative cancers. In the case of hormone receptor-positive cancers, we’ve known for some time that drugs we use to treat advanced- and early- stage cancer, such as tamoxifen and aromatase inhibitors, can also lower the risk of contralateral new breast cancers, and the concept of prevention has now been tested extensively in numerous randomized trials. Most of these have been with tamoxifen, and more recently with raloxifene in postmenopausal patients. These studies have shown that you can reduce the risk of developing breast cancer by half, and with raloxifene, some of the side effects, including endometrial cancer and deep venous thrombosis, are much less prevalent than with tamoxifen. Still, these drugs are used very infrequently in clinical practice for prevention, in part because patients and physicians are concerned about side effects, but also because it is difficult for us to precisely pin down who is at risk for breast cancer.

From your perspective, what does the future hold for the breast cancer field?

Needless to say, there are still plenty of challenges ahead. One of the most difficult areas is that of triple-negative breast cancer. In early stages, we know that it is a more aggressive cancer. Can we find more effective therapies? We now typically use anthracycline and taxanebased therapies for some patients or nonanthracycline therapies in some cases in the adjuvant setting. This clearly does lower the risk of recurrence. However, we’re looking for newer targeted drugs. If you look at the conventional drugs that are being tested in this area—for example, capecitabine in the adjuvant setting— there’s a hint that in triple-negative cancers there may be some effectiveness when added to standard anthracyline/taxane regimens; however, they come at the cost of added toxicities. The main outcomes of these studies need to be followed a little further, because when you look at the main intended statistical analysis, they’re still negative studies. So, we still haven’t quite found a way to improve upon where we are in the adjuvant setting.

There’s been a lot of excitement about PARP inhibitors in triple-negative breast cancers, and there are now PARP inhibitor trials in the adjuvant setting, as well as in the metastatic setting. One of the lead PARP inhibitors, iniparib, led to very profound results in the phase II setting that were not quite replicated in the phase III setting. This was a large study led by O’Shaughnessy and colleagues that tested gemcitabine and carboplatin with or without iniparib. Iniparib did show an impact in second- and third-line treated patients, but it was not as dramatic. I believe that we still need to look at these data to see if there may be a subset of patients who might benefit. It also turns out that iniparib is a rather weak PARP inhibitor. It clearly has other activities on DNA damage that need further study, and these studies are ongoing in both the laboratory and the clinic. Other PARP inhibitors like veliparib and olaparib also have not led to the dramatic results we were hoping for. Initially, these drugs were showing effectiveness in advanced cancers, especially cancers that were BRCA1/2-related, because PARP inhibitors inhibit one of the legs of DNA repair, and BRCA1/2 mutation-containing tumors already have a defect in double-stranded DNA repair. It was felt that, through the use of these drugs, a socalled “synthetic lethal effect” could be seen.

So, the final story on PARP inhibitors has yet to unfold. We need to await completion of the ongoing trials. But, at the same time, we need to expose other vulnerabilities in triple-negative breast cancers. There’s been some interesting work done with androgen receptors, which are expressed at a higher frequency in this group of patients. Using androgen receptor blockade with drugs used for prostate cancer has shown evidence of activity in preclinical studies, and these trials need to be pursued further in clinical trials, which are ongoing. There’s also the capacity to reinduce some of the silenced genes using histone deacetylase inhibitors and DNA methyltransferase inhibitors such as 5-azacytidine. These concepts are in early-phase trials and are being studied vigorously. We still need to crack the code on triple-negative breast cancer. It clearly is a distinct entity. In fact, there are several sub-entities, and we need to start to delve into the heterogeneity of this cancer type.