Editor's Note: Metastatic breast cancer, the incurable form of the disease, takes a back seat at pink ribbon promotions where the emphasis is on cure. But metastatic disease does not take a back seat in research, where greater understanding of biology is giving rise to new therapies that extend survival. Unprecedented survival was reported for patients with metastatic HER2-positive disease when the final results of the CLEOPATRA trial were published recently by Sandra M. Swain, MD, and colleagues[1] in the New England Journal of Medicine. Medscape spoke with Dr Swain, medical director of the Washington Cancer Institute and professor of medicine at Georgetown University, for her insight on strategies that offer the richest promise of clinical progress in metastatic breast cancer.
Medscape: Why should we conduct research in metastatic breast cancer?
Dr Swain: Once a cancer has metastasized, it can be challenging to treat. Many of the solid tumors, such as those of the breast, lung, and colon, become incurable once they metastasize, so we obviously need to have more effective treatments in order to prolong life. We have made a lot of progress and new therapies are continuously being developed, but we are not where we'd like to be. And though we do have a lot of good treatments, there is considerable toxicity associated with many of them. Toxicity can limit patient adherence and efficacy if the dose needs to be reduced or the treatment interrupted because the patient cannot tolerate it. We want to improve on that. We need to continue doing research in metastatic breast cancer to develop treatments that are more effective and with a lower burden of toxicity.
Medscape: Some argue that in an era of limited resources we should put less emphasis on metastatic disease and more on patients with potentially curable disease.
Dr Swain: I would hope that we think about any cancer as potentially curable. That said, we definitely need to keep funding not only clinical research but also basic science research. In basic science is where the drivers of cancer and the targets are being identified, and knowledge of those will allow us to develop effective drugs. This aspect of cancer research is incredibly important, because it leads us down the right path to effectively treat these patients.
We have come a very long way in developing targeted treatments that are effective in several small populations. Examples are the ALK inhibitors in lung cancer, which were developed for patients with ALK mutations and translocations.[2,3] Patients in these groups have responded very well to these agents, and we have also seen this in breast cancer patients with HER2-positive disease, with the advent of targeted therapies such as trastuzumab.[4] Patients with HER2-positive breast cancer used to do very poorly, but now they are living for many years with advanced disease. But people still do die of breast cancer.
Is a Cure Out of the Question?
Medscape: Are we getting closer to curing patient with metastatic disease, rather than just extending survival?
Dr Swain: We would love nothing more than to find a cure. With any of the treatments we have now, we hope that each might cure the patient. But these cancers are incredibly "smart"; they develop different mutations and find alternate pathways and different ways to continue growing.
There is a lot of interest in developing treatment regimens that combine different targeted therapies[1,5-9] that can halt the growth and perhaps cure the patient. We are striving for that.
Medscape: Recap for us several of the studies that have made the strongest impact on treatment of metastatic breast cancer.
Dr Swain: The CLEOPATRA study[1] has made a huge impact thus far in showing that survival can be increased. In that trial, pertuzumab added to trastuzumab and docetaxel significantly improved overall survival for patients with HER2-positive metastatic breast cancer. The median overall survival of about 4.5 years is unprecedented in the first-line setting.
Another study that has made a big impact is the PALOMA-1, a randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone. The study results were recently published in the Lancet Oncology[10] and showed that adding palbociclib to letrozole significantly improved progression-free survival in patients with ER-positive and HER2-negative disease. Palbociclib, which is an oral agent, is a very exciting drug in combination with hormonal therapy, and it was approved by the US Food and Drug Administration in February for metastatic ER-positive breast cancer.
There are several very early trials in immunotherapy that were recently presented at the San Antonio Breast Cancer Symposium, looking at PD-1 and PD-LI inhibitors in metastatic triple-negative breast cancer.[11,12] There were hints of activity, but these are very early data.
Strategies to Lower Toxicity, Improve Quality of Life
Medscape: You mentioned the need to not only develop effective treatments but also to find ways to lower the patient's burden of toxicity. What changes in practice have improved the quality of life of patients with metastatic disease?
Dr Swain: Chemotherapy is associated with varying degrees of side effects, and the agents commonly used in metastatic breast cancer are no different. One method of reducing toxicities is to use different partners with the monoclonal antibodies, such as using a taxane drug that might be more tolerable for the patient. There are also new supportive therapies in development. A study of olanzapine has shown it to be helpful in treating the nausea and vomiting associated with chemotherapy.[13]
Importantly, we are looking at ways to improve quality of life. A large number of oral drugs have become available to treat different types of tumors. In metastatic breast cancer, this is still largely limited, but we are developing oral agents such as palbociclib. Many patients prefer oral drugs over intravenous infusion, and this can improve their quality of life.
Quality of life is becoming more of a priority in clinical trial design. Patient-reported outcomes are increasingly important. We want patients to be involved in the decision of what degree of toxicity they are willing to bear, and what benefit they are looking for. We are seeing more trials designed to incorporate that data. Patient advocacy groups have become more vocal on this subject, and I think they are right.
Changing the Clinical Trial Paradigm
Medscape: What studies should be done to more effectively treat patients with metastatic disease?
Dr Swain: We are doing a lot of different types of trials. So-called "umbrella trials" enroll patients who have the same type of cancer but differing molecular mutations, and patients are placed into a treatment arm on the basis of the molecular makeup of their tumor. These studies have many different arms under the umbrella of a single clinical trial. An umbrella study allows us to test a variety of targeted therapies at the same time in patients who are most likely to derive a benefit.
In "basket trials," new treatments designed for a specific genetic defect in a tumor are tested on multiple cancer types. For example, colon cancer patients and ovarian cancer patients are assigned to their own baskets, or arms, of the study. The advantage of this strategy is that it allows for new therapies to be evaluated in different tumor types.
That is the wave of the future—to look at the genomics and proteomics and all of the aspects of the cancer, and then try to find the mutation that really drives the cancer. By targeting the drivers of the cancer, we can hopefully prevent further growth of the tumor.
Right now we are seeing quite a few of these pathway trials. For example, the Signature trials that Novartis is doing[14] are linking targeted therapies to patients with pathway-activated tumors. The patients all have different types of cancers, and they will receive investigational agents that are targeted to match the genetic alteration in their individual tumors.
But what we really need are more patients to participate in these trials, because that's the only way we are going to understand the pathways and how well these new targeted drugs work across cancer types. For example, in colon cancer, melanoma drugs aren't effective even though they have the same mutation. We really need to have studies to show us what works and what doesn't.
Converting a Killer to a Chronic Disease
Medscape: Where are we heading in future treatments for metastatic disease?
Dr Swain: One of the more interesting concepts, and one that is getting a lot of attention, is looking at the circulating DNA and doing what we call liquid biopsies. There are noninvasive blood tests that detect circulating tumor cells and fragments of tumor DNA that are shed into the blood from the primary tumor and from metastatic sites.[15] They can be used for diagnosis, response to treatment, and prognosis and are much easier for the patient than having to undergo repeated scans or invasive tissue biopsies. In the future, liquid biopsies could be very useful in monitoring tumor changes in real time and could help guide cancer treatment decisions.
In metastatic disease, we do recommend that biopsies be done more frequently because the tumor can change, and that's where the liquid biopsy may be more helpful. A patient's tumor can have a change in the mutation, for example. It can sometimes be very difficult or impossible to do a biopsy at some sites, such as if the cancer has metastasized to the bone.
Medscape: Is it possible that even metastatic breast cancer may eventually be viewed as a chronic disease?
Dr Swain: Currently, metastatic breast cancer is incurable, and the only thing we can do is to keep treating our patients with the best we have. We would love to be able to cure this disease. But aside from finding a cure, I would like to see it evolve as AIDS did. AIDS was once a death sentence but now has become very treatable, with people living very long and normal lives. I hope metastatic breast cancer evolves in that way. We are seeing hints of that in new and effective therapies, and we are seeing great responses that are long-term.
References
Swain SM, Baselga J, Kim SB, et al, for the CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-734. Abstract
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566. Abstract
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703. Abstract
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792. Abstract
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (neoSphere): A randomised, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. Abstract
Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585-2592 Abstract
Ellis PA, Barrios CH, Im Y, et al. MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 3-7, 2011; Chicago, Illinois. Abstract TPS102.
Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640. Abstract
Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T+L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Program and abstracts of the American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago, Illinois. Abstract LBA4.
Finn RS, Crown JP Lang P, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35. Abstract
Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Program and abstracts of the 2011 San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S1-09.
Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Program and abstracts of the 2011 San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract PD1-6.
Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21:1655-1663. Abstract
Dawson SJ, Tsui DWY. Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199-1209. Abstract
