Breast Cancer Leaders Reflect on Progress

This year we are celebrating the 20th anniversary of our flagship publication OncologyLive. To mark the occasion, we are asking oncology leaders to reflect on the tremendous progress made in cancer research and practice over the past 2 decades. Here are insights from 4 of the top thought leaders in the field of breast cancer.

MARK D. PEGRAM, MD

Stanford Women’s Cancer Center

Mark D. Pegram, MD

HOW HAS BREAST cancer treatment changed in 20 years? Night and day. We can now sequence whole genomes in breast tumors. We can measure allelic frequencies of particular mutations. It’s been a sea change in technology. The intrinsic subtypes of breast cancer were discovered at Stanford based on gene expression technology, which was pioneered at my institution back in the early 2000s. We didn’t know there were different intrinsic subtypes; as clinicians, we knew they must exist, because some patients did very well with standard treatment in early-stage disease and some relapsed and died of early-stage breast cancer—and still do, to this day. The question was always “Why?”

Back when I first started my training, we treated most people based on their stage and steroid-receptor status and that was about it. And then came HER2 and the first biologic agent ever approved for breast cancer, trastuzumab. There have been changes in the treatment of hormone-receptor positive breast cancer. Look at the multigene testing platforms that are commercially available; all those platforms are, ultimately, based on gene expression array technology. The multigene platforms can now [identify] groups with such good prognosis that they don’t need chemotherapy. That was a huge change in the practice of breast cancer, and I saw it during my lifetime. I never expected to see that kind of classification of human breast cancer—to such granularity. That is just the first generation of the multigene test. There will be future generations exploiting this kind of new genomic age technology, which will divide breast cancer in to more granular subsets that no doubt will have both prognostic and predictive value in those categorizations.

WILLIAM J. GRADISHAR, MD, FASCO

Northwestern University Feinberg School of Medicine

William J. Gradishar, MD

TWENTY YEARS AGO I chaired the NCCN [National Comprehensive Cancer Network] Guideline panel and if you look back at the NCCN Guidelines for breast cancer you would be struck by how simplistic they were. It was not because we were dumb; we just did not have much to work with. There was nothing on the guidelines beyond tamoxifen. [Oncologists] stratified risk in early disease based on the nodes: 0, 1 to 3, or more than 4. There were no molecular tests; no one even knew what they were. There was no HER2. As a consequence, when you looked at the adjuvant therapies, they tended to be antihormonal therapies with tamoxifen or a couple of chemotherapy regimens in metastatic disease. We had a few more chemotherapy drugs, we had a couple of hormone therapies, and that was it.

Now if you look at the guidelines and the time period between, we have gone through a lot of [changes]. [At one time] bone marrow transplant was going to cure breast cancer. It did not do that, and it took us off track for a while. We have evolved in our understanding of molecular biology and interrogating tumors and that resulted in the development of newer antihormone therapies [such as] the aromatase inhibitor fulvestrant. In the HER2 space, which we did not acknowledge or recognize 25 years ago, we now have a plethora of new drugs, including trastuzumab, pertuzumab, neratinib. Many more are being developed.

Chemotherapy options have increased, but what has really changed more recently is the addition of targeted therapy and how we are employing that in treating patients. Furthermore, I think, the nuances of surgery have changed completely. Lumpectomy and sentinel node biopsy are the preferences. We have really made incredible advances. In certain areas, such as triple-negative disease, the role of checkpoint inhibitors and immunotherapy holds promise. I think if we continue on this path, 20 years from now [future generations] will look back on what we have as nothing compared with what they have.

HOPE S. RUGO, MD

University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center

Hope S. Rugo, MD

BREAST CANCER THERAPY has gone through an entire revolution over 20 years. We had aromatase inhibitors in the metastatic setting, but [their use as treatment] for stage began within that time frame. HER2 therapy with trastuzumab [Herceptin] started 20 years ago, and then within those 20 years, we saw that we could change survival by giving trastuzumab to patients with early-stage breast cancer and that we could sometimes have patients who have long-term survival in metastatic disease with trastuzumab. And, of course, the add-on drugs since then have continued to improve survival for patients with HER2-positive disease. In the hormone arena, we moved on from aromatase inhibitors to fulvestrant [Faslodex] and then on to better dosing and scheduling of fulvestrant, which helped us better understand that some patients might actually benefit more from fulvestrant than from aromatase inhibitors.

Moving forward in this very, very exciting field of targeted agents we saw the first mTOR inhibitor everolimus [Afinitor], the explosion of CDK4/6 inhibitors, and the α-specific PI3K kinase inhibitor alpelisib. More recently, an explosion has occurred in understanding immunotherapy for triple-negative breast cancer and expanding that knowledge to other disease subtypes to try to understand how we can best use these therapies in this disease. The other thing that we have learned in the past 20 years is that people who get a pathologic complete response from neoadjuvant therapy have a very good chance of being cured of their cancer. We can give people a better prognosis and potentially better therapy by treating patients who have more proliferative ER [estrogen receptor]—positive, HER2-positive, and triple-negative breast cancer in the neoadjuvant setting.

More recently, we have learned that for patients who did not get a pathologic complete response, we can alter their outcome by giving them other therapies. Those are very recent data, which further strengthen the role of giving therapy in the neoadjuvant setting. Lastly, the past 20 years have brought a big explosion in supportive care. We have been able to offer patients supportive care that we didn’t have before. It’s amazing to think that the widespread use of growth factors—for example, the long-acting myeloid growth factor pegfilgrastim and the rise and fall of erythroid growth factors—and the use of dose-dense chemotherapy have been largely in the past 20 years. And then, more recently, [came] scalp cooling, an area that I’ve been quite passionate about, and being able to prevent mouth sores from everolimus with a steroid mouth wash—all of this, plus studies that have looked at ways to prevent hot flashes with a lot of different agents, really dig back about 20 years.

DEBU TRIPATHY, MD

The University of Texas MD Anderson Cancer Center

Debu Tripathy, MD

IN 1998, I HAD my first visit with the oncology drugs advisory committee, ODAC, which advises the FDA, because we were presenting data on trastuzumab. At the same session, the tamoxifen prevention data were being presented. That was really an important mark in breast cancer, where HER2-tar-geted therapy results were presented from randomized trials. Since that time, we have had a lot of different breakthroughs. There has been a lot of work going on in inherited genetics—what drives the beginning of cancer. Right around that time is when the BRCA1 gene was cloned and shortly after that, BRCA2.

The whole area of genetic testing and genetic counseling became main-stream in our practice. Initially it was used mostly for identifying people at risk and putting them under more cautious surveillance and for surgical prevention, espe-cially for [patients with] ovarian cancer, which is difficult to detect early. That has made a big difference. More recently, we realized that these tumors are biologically different and they respond to different drugs. Now 2 PARP inhibitors have been approved—most recently, olaparib and talazoparib for BRCA1/2 mutation—related cancers. Other important advances include things that allow us to do less surgery, and that is a big factor for anybody who [receives a diagnosis of] breast cancer. There are studies going on now to see if we can eliminate surgery by using neoadjuvant therapies and testing patients for any residual cancer; maybe they don’t have to have surgery. Radiation has also undergone some innovations and more focused targeted therapies—things like partial breast radiation, which seems to be adequate for certain cases, and giving radiation in less time, shrinking it down from 6 weeks to 4 or even less using hypofractionation. In triple-negative breast cancers, we now know that patients who do not respond to chemotherapy and have residual tumor at the time of surgery have a much higher risk, and we now know that capecitabine, a chemotherapy drug, can make a difference.

The area I expect to see much more movement in is immunotherapy. Just this year we had an important milestone, with the first randomized trial showing an improvement in survival in patients with PD-L1—positive triple-negative breast cancers, and this is the beginning of more innovations with immunotherapies. We still need things for patients whose tumors are PD-L1 negative, which is about 60% of triple-negative breat cancer patients. We need to see if immunotherapy is effective in HER2-positive and in hormone receptor–positive cancers. My sense is that we are going to need combination immunotherapies in which we use different ways to modulate the immune system and other aspects of cell signaling and those trials are under way now.