Blackwell Explores Emerging Trends in Treating HER2 Metastatic Breast Cancer

Kimberly L. Blackwell, MD

Since its approval in 1998 to treat metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab has dramatically expanded life expectancy and improved quality of life for women diagnosed with HER2-positive disease. It remains the standard-of-care, first-line treatment for metastatic breast cancer. In less than a decade, the FDA has added three new drugs to the arsenal to treat advanced HER2-positive disease, while a growing number of clinical studies are evaluating dual-agent approaches to therapy through a variety of drug combinations.

At the MBCC mini-symposium, Kimberly L. Blackwell, MD, the director of the Breast Cancer Program at Duke Cancer Institute, discussed current treatment options in a presentation entitled “Targeting HER2 in Metastatic Breast Cancer in 2014.” She put emerging treatment trends into context during an interview in advance of her talk.

How have treatment options and prognoses changed over the past decade for women diagnosed with HER2-positive breast cancer?

We can no longer speak of diagnosing breast cancer in broad terms, but rather of different subtypes of breast cancer and cancer stage. Prognoses, based on a specific cancer’s biology, are very different. But we can say that the prospects for women diagnosed with HER2-positive breast cancer have improved. With certain subtypes, discovered in the early stages of the disease, we can start talking about a cure. This marks a paradigm change; we could not have said this 10 years ago. There are now people with HER2-positive disease who have no recurrence if they are treated earlystage with trastuzumab. The prognosis for these women is pretty tremendous, and it has allowed us to save years and years of life for them.

How have prospects changed for women with HER2- positive metastatic disease?

There are a lot of options for these women if their cancer remains HER2-dependent. We now treat metastatic breast cancer as we would a chronic disease, such as diabetes or heart disease, with targeted therapies and combinations of therapies.

A serious challenge we face with some of these women, however, is brain metastases. This is a tragic situation, especially for women who have lived a high-quality life for several years and then develop metastases. It is a difficult cancer to treat, and these patients may also suffer the long-term effects of stroke. We must recognize that we aren’t able to adequately treat progressive brain metastasis.

Where are the post-trastuzumab drugs proving most effective, and in what settings?

The approval of T-DM1, an antibody-drug conjugate, is changing the way we care for metastatic breast cancer and solid tumors in general. Treatment that doesn’t hurt the immune system is a major breakthrough that will improve patient care. Lapatinib is not super effective therapeutically. We see that lapatinib and trastuzumab are more effective together than lapatinib alone. But there may be new life for this drug. The data we have now do not look at combinations with T-DM1 or the effect of layering trastuzumab with lapatinib or pertuzumab.

What role are dual-agent therapies playing in the treatment of metastatic disease?

We’re doubling down on HER2-positive cancer. There will be few studies from now on that evaluate trastuzumab alone; in metastatic breast cancer, dual agents are here. The dilemma facing clinicians over the next 5 years is going to be sequencing.

How do the newer drugs improve upon the performance of trastuzumab?

There is a limited ability to improve upon trastuzumab’s performance with these newer drugs. There are studies whose results we’re anxiously awaiting, but it’s really unclear how useful they will be. With healthcare reform and the cost to society of developing and prescribing new drugs, we need to look very carefully at the value of small incremental gains and to ask some very hard questions as a society: Is it worthwhile to add new medications? How many people need these new expensive therapies?

Are there drugs on the horizon that may improve treatment for HER2-positive disease?

Everolimus [approved in HER2-negative settings] may prove valuable. While it showed only a small improvement in progression-free survival in BOLERO-3 (1.2 months), I don’t dismiss it. I think its capacity to cross the blood-brain barrier is important and it may prove useful in addressing brain metastases. I think we will also see neratinib come to the table. We saw in the I-SPY 2 study of neratinib in the neoadjuvant setting that it met its primary endpoint. I think that studies of PI3-kinase inhibitors are also going to yield some interesting results.

What role do you see for a vaccine?

This is the therapeutic area I’m most excited about now. If trastuzumab can make such a difference and it’s a monoclonal antibody, we can only imagine what a polyclonal response would be like. A proven vaccine in the HER2-positive sphere would have a huge impact. The obstacle to a vaccine is that it’s hard to develop. We would also need to figure out which patients are capable of mounting an immune response, which aren’t, and then determine how to screen for that.

Which clinical studies stand to have the largest impact on the direction of treatment?

In metastatic disease, we are waiting for full results from MARIANNE, which for the first time evaluates whether T-DM1 alone or combined with pertuzumab is better than trastuzumab and a taxane. This could [establish T-DM1] as a first-line therapy in metastatic disease, and so MARIANNE is a game-changing study. The APHINITY trial, [which compares trastuzumab plus chemotherapy with and without pertuzumab as adjuvant therapy for primary breast cancer] will also be important. A question for clinicians going forward will be whether to choose pertuzumab or lapatinib in the adjuvant setting. This will be a dilemma, and the answer will be driven by patient-reported outcomes.

How effectively are we diagnosing and treating molecular subtypes of breast cancer?

We now have the capability to look at 50 genes linked with breast cancer. What’s missing is not the ability to accurately characterize cancers through diagnostic testing, but the infrastructure that allows practicing doctors to do this and then select appropriate treatments for their patients based on it. We need to have a transparent dialogue about what’s holding up getting this capability to the clinic, and then to forge a commercial/academic partnership to get it done. It will be important to develop an assay that we can all use regularly, and I believe there should be financial incentives to deliver this assay. I use the Oncotype DX test because I feel it helps me take better care of my patients.

Concerning the need for biopsies, my least favorite word is “optional”:⎯It makes the choice sound unimportant. It’s essential to know what sort of tumor a patient has. We do not want to be in the position of telling a patient that we didn’t have the impact we’d hope to have on her cancer because we didn’t know what it was. If I tell a patient I want to know what’s driving her tumor forward, she will almost always agree to a biopsy. They do have a cost, but treating a patient with a drug that won’t help them is also costly. This applies to clinical trials as well. We have no ability to say which subsets of patients benefit from a medication if we don’t collect tumor biopsies and figure it out.

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