Tripathy Offers Perspective on HER2-Positive Breast Cancer

Debu Tripathy, MD

The ever-evolving treatment landscape for patients with HER2-positive breast cancer leaves several questions unanswered regarding therapeutic sequences and whether an optimal standard of care exists. To provide further perspective on current paradigms, OncLive interviewed Debu Tripathy, MD, a breast cancer expert whose clinical research efforts focus on novel therapeutics, resistance, and the discovery of biomarkers.

Tripathy, a professor of medicine and the co-leader of the Women's Cancer Program at the University of Southern California Norris Comprehensive Cancer Center, serves as the primary investigator for the Systematic Therapies for HER2-positive Metastatic Brest Cancer Study (SystHERs), which hopes to provide information on treatment patterns across the United States.

OncLive: The SystHERs registry hopes to answer several questions, can you describe this study?

Tripathy: The SystHERs registry study is a registry that is enrolling patients who have been diagnosed with HER2/neu-positive metastatic breast cancer within the last 6 months. It’s an effort to collect detailed information on patients who are diagnosed with HER2 metastatic breast cancer to look both at the demographic factors as well as their past history: when they’ve presented with early stage disease, what treatment they got. The registry also looks at what treatment they receive in the metastatic setting, what their outcomes are in terms of response and side effects.

One thing that’s important about this registry is that we don’t have information as to how patients are treated and followed after their diagnosis. We have data from individual trials, which covers them through one course of treatment, but to put together the whole picture regardless of what their treatments are is really not known. And now that there are new agents to treat metastatic breast cancer in the HER2-positive setting we need a better handle on how patients do in the long time course, because clinicians need to face complicated treatment decisions in patients who have had a variety of different prior treatments.

And so what we are looking to do with this registry is to be able to analyze long-term information. We intend to enroll 1000 patients and we intend to follow patients for 8 years so we will have a lot of longitudinal data.

What will be the important take-away points from SystHERs?

Well, the reason that we are looking at this is to look at how patients do through a sequence of therapies as opposed to just one individual course, which is what the clinical trials address. This project will also look at the rarer toxicities that may not be apparent from the individual trials but might surface in a larger trial that has longer follow up.

We also want to look at how decisions are made for both toxicity and treatment. We want to gather patient-reported outcomes, which is another feature of this registry. We give patients questionnaires about the quality of life and the symptoms they’re having. This is also something that we don’t have a lot of information on.

Finally, we are asking patients to consent to submit blood as well as tissue from previous surgeries and biopsies so that we will be able to look at biomarkers as well.

What are the current frameworks used for decision-making and sequencing for patients with HER2-positive metastatic breast cancer?

There are some broad frameworks that physicians use based on the trials but many patients don’t fall into the broad frameworks and may not fit very easily into a particular decision algorithm.

For example, we now know that in the first-line setting, for patients who have not had any previous trastuzumab or had adjuvant trastuzumab over a year ago, the best treatment as far as we can tell from clinical trials is a combination of trastuzumab and docetaxel or possibly other taxanes. While many patients may fit into that category, the question is “what do you do next when they progress?”

We know that T-DM1 is superior to other therapies such as capecitabine and lapatinib, which used to be the prior standard, but again, what do you do when a patient progresses in a very short period of time? And then what do you do after second-line therapy? What do you do in the third, fourth, and fifth-line setting? There we have very little guidance so we can go by data from phase II trials and if you look at the NCCN recommendations, for example, they will cover a handful of combinations. But there really is no way to know which is best for any given situation.

Is preoperative therapy the standard of care for HER2-positive disease?

Preoperative therapy for early stage non-metastatic breast cancer gives the same long-term results as postoperative therapy in terms of recurrence and survival. But it does offer the advantage of being able to shrink the tumors. So for some patients, it may be indicated if it increases their chances of being able to have breast-conserving surgery or if the surgeon feels that getting negative margins might be difficult. For example, a patient that has skin involvement or a patient that has an extremely large tumor, in those settings, neoadjuvant therapy probably offers some advantages.

Now, in HER2-positive disease, we now know that when we add pertuzumab to standard trastuzumab-based therapy that the complete pathologic response rate is clearly improved. And so that has now been an FDA-improved indication to use pertuzumab in combination with either docetaxel and trastuzumab or other chemotherapies with trastuzumab because of the higher complete pathologic response rate. Now we don’t know at this point that those patients will have a better survival or a lower chance of developing metastases, those trials are still pending but the FDA has recently looked at the complete pathologic response rate as one criteria of others that might lead to an indication in the neoadjuvant setting.

Right now, for patients that have tumors that are greater than 2cm or with positive nodes, there’s actually an FDA indication to use pertuzumab. But again, it’s important to emphasize that the outcome here is a higher complete pathologic response rate. We don’t yet know that it’s going to result in improved survival like it does in the metastatic setting.

Looking ahead, what breast cancer research are you most anticipating?

I think that using combinations of therapies that are intelligently designed to circumvent resistance is very exciting. For example, in the HER2 space, most patients will eventually progress on a given therapy and we need to understand why they progress, what are the genes that actually drive the resistance? What are the proteins that drive it? Can we develop drugs against those? And then, if we know that resistance may develop through that pathway, should we be treating patients upfront with a combination?

We know that in certain cancers like testicular cancer and hematologic cancers we’ve been able to cure metastatic cancers by combining drugs. But with most solid tumors, the number of genetic mutations is just too high to use chemotherapy over a single targeted drug.

So I think this is the next frontier in designing rational combinations that are personalized based on the unique tumor set of pathway a person might have.