Illustration by Anna Godeassi © 2018.

In 2017, more than 63,000 women in the United States were diagnosed with in situ breast cancer. The overwhelming majority of those women, about 83%, were diagnosed with ductal carcinoma in situ (DCIS), a condition characterized by the presence of abnormal cells confined to the breast milk ducts; and about 13% were diagnosed with lobular carcinoma in situ (LCIS).¹ Both entities are also sometimes referred to as “precancer” or stage 0 breast cancer. And although DCIS will not become a life-threatening disease for most women—between 20% and 30% of women with the condition will develop invasive breast cancer—current guidelines call for all women with DCIS to be treated with some combination of surgery, usually lumpectomy, and in some cases mastectomy or prophylactic mastectomy; radiation therapy; and years of hormonal therapy. 

Although the goal of these treatments is to prevent breast cancer recurrence and mortality, increasingly some women and oncologists, concerned about the side effects of overtreatment, are questioning the necessity of such aggressive therapy for the majority of women who will never develop invasive cancer; they are instead opting for active surveillance, or watchful waiting, as an effective alternative to monitor signs of disease progression over time. 

The question of which patients would most benefit from immediate treatment and which ones could be safely managed with active surveillance is raising a dilemma for both patients and physicians about how DCIS should be monitored and how (or whether) it should be treated. The answers could come over the next decade, as results from a trio of trials for this type of low-risk breast cancer—two in Europe, LORD (ClinicalTrials.gov identifier NCT02492607) and LORIS (www.birmingham.ac.uk/research/activity/mds/trials/crctu/trials/loris/index.aspx) and one in the United States, COMET (ClinicalTrials.gov identifier NCT02926911)—provide a clearer understanding of how best to manage these patients. 

Shelley Hwang, MD, MPH

Ann H. Partridge, MD, MPH

Lawrence J. Solin, MD

To learn more about the current treatment strategies for DCIS; how to tailor treatment based on tumor characteristics; and how the results from the COMET trial could alter how DCIS is treated, The ASCO Post held a roundtable with three leading breast cancer experts. The panelists include Shelley Hwang, MD, MPH, Professor and Vice Chair of Surgery at Duke Cancer Institute in Durham, North Carolina, and principal investigator of the COMET trial; Ann H. Partridge, MD, MPH, Professor of Medicine at Harvard Medical School, a medical oncologist at Dana-Farber Cancer Institute in Boston, and co–principal investigator of the COMET trial; and Lawrence J. Solin, MD, Emeritus Professor of Radiation Oncology at the Perelman Center for Advanced Medicine at the University of Pennsylvania and Chairman of the Department of Radiation Oncology at the Albert Einstein Healthcare Network in Philadelphia. 

Defining Stage 0 Breast Cancer 

DCIS is often called precancer or stage 0 breast cancer. How would you define abnormal cells in the breast? Are these abnormal cells precancer or cancer, or are they more a risk factor for developing cancer? 

Dr. Hwang: DCIS lies in the spectrum between benign disease and invasive cancer. Other diagnoses in this continuum include atypical hyperplasia, columnar cell hyperplasia, and LCIS. Some precursor lesions have a high risk for subsequent invasive events, and others have a relatively lower risk, but women who have one of these diagnoses have a higher risk for invasive disease than those who have never had one of these conditions. 

DCIS is clearly one of those diagnoses with a higher risk for a subsequent invasive event, and we are developing better tools to know which subtype is more likely to be associated with an invasive progression. A lot of work is being done, including in our lab, to look for the molecular characteristics that would help us tease apart low vs high risk, but there remains a large range of uncertainty with molecular markers. Consequently, women always think they are on the high side of that uncertainty and will make their treatment decisions accordingly, so those tools have not been as helpful as they should be to incorporate them routinely into clinical care. 

“It is important for women to have the freedom to choose what they feel is the best balance between treatment and treatment-related morbidity.”

— Shelley Hwang, MD, MPH

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Dr. Partridge: The answer is all of the above, and all these views are valid, but they convey different threats to patients, so how we label DCIS matters. I don’t think we should stop calling it stage 0 cancer, but we have to be careful about how we talk to patients about their choices for treatment and the true benefits and risks of those treatments.

Patients are understandably in a state of distress when they are diagnosed with DCIS, and physicians sometimes treat the condition as if it were a medical emergency, so there is a lot of confusion and amped-up risk perception. Most women will not develop invasive breast cancer after a diagnosis of this low-risk breast cancer, but we have few data on what proportion of women would develop invasive disease if left untreated; we don’t usually watch DCIS, we treat it, and that has brought us to the COMET trial. 

A parallel trial, PORTAL, aims to evaluate how women diagnosed with certain breast conditions, including DCIS, feel both physically and emotionally after a breast biopsy. We hope to obtain more data on the longer term outcomes of women treated or not treated for DCIS or one of the other “precancerous” risk markers that are not likely to become invasive disease. 

Dr. Solin: I agree. DCIS is both a non-obligate precursor and a risk factor for developing invasive breast cancer. The nomenclature referring to DCIS as stage 0 cancer has been around for a long time, and there have been discussions about whether it should be changed, but for the moment this is the standard nomenclature. 

Controversy Surrounding Treatment 

Many women diagnosed with DCIS are opting for aggressive therapy and mastectomy, although most will never develop invasive breast cancer. Please discuss the controversies surrounding the treatment of these women. 

Dr. Hwang: It really gets distilled down to how people view their risk of cancer and who decides whether that risk is high or low. Throughout the history of breast cancer treatment, any risk that was higher was considered an inferior option, and we’ve never tried to balance that risk against the downside of treatment side effects. Historically, we as physicians have always recommended treatment with the likelihood of providing the lowest risk of recurrence—full stop. However, recurrence may not be the only outcome that is important to the patient, or what is medically prudent, particularly in patients with competing comorbidities. 

Surgery and radiation therapy are not without side effects. Side effects from radiation are infrequent, but radiation has been associated with cardiac and pulmonary sequelae as well as rare secondary cancers. Mastectomy may cause long-term physical and emotional problems. The contention that we and others are making is that there is risk both with treatment and with treatment de-escalation, and we need to be able to quantify that trade-off in a much better way for an individual patient. 

It is important for women to have the freedom to choose what they feel is the best balance between treatment and treatment-related morbidity. We’re not giving them the full range of options right now because often we’re treating all patients as if they have a life-threatening illness and giving them recommendations that go along with that perspective. 

Dr. Partridge: As we’ve discussed, there is a great deal of uncertainty regarding the risk of DCIS becoming an invasive cancer in a specific patient. We know it is not likely to threaten a woman’s life, although there are exceptions. When a woman is treated for this type of breast cancer and the disease comes back, it could threaten her life as invasive breast cancer. But when you look at studies of women who have been treated for DCIS and the few data on women who have not been treated, in both groups, overall, the women do extraordinarily well in terms of survival. 

So the question is not necessarily about treating the disease but about risk reduction. We do a lot of treatment for DCIS. Fortunately, we do not give chemotherapy outside of a clinical trial in which targeted agents are being tested. But we do perform surgery and prescribe radiation therapy and suggest women take hormonal therapy, all of which can have a big impact on women’s quality of life. We are hoping the results from the PORTAL trial will give us more information on the true harms of such treatment. 

“Some women don’t want to risk invasive cancer because DCIS can essentially be cured for many with surgery.”

— Ann H. Partridge, MD, MPH

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I don’t mean to say we should just let patients do whatever they want for the treatment of their low-risk lesions, but I want patients to understand their options and to have choices. Clearly, there are some decisions that are ill-advised or overkill to the point where it is not the medically right thing to do. We first have to do no harm and do the right thing for patients. 

Dr. Solin: We need to tailor therapies better for individual patients. In terms of surgery, there is a wide range of options from lumpectomy to mastectomy and even bilateral mastectomy for high-risk patients. For women who undergo lumpectomy, the question is whether they also need radiation and hormonal therapy, and the problem is that we overtreat the many to benefit the few. And although this is a well-accepted strategy for invasive cancer, for a noninvasive cancer that is not life-threatening, it is a much more difficult risk/benefit ratio to deal with, which is why physicians are talking about de-escalating therapies. 

We need to tailor therapies better for individual patients. In terms of surgery, there is a wide range of options from lumpectomy to mastectomy and even bilateral mastectomy for high-risk patients. For women who undergo lumpectomy, the question is whether they also need radiation and hormonal therapy, and the problem is that we overtreat the many to benefit the few. And although this is a well-accepted strategy for invasive cancer, for a noninvasive cancer that is not life-threatening, it is a much more difficult risk/benefit ratio to deal with, which is why physicians are talking about de-escalating therapies. 

Altering How Radiation Therapy Is Prescribed 

Has the controversy surrounding how best to treat DCIS changed the way you prescribe radiation therapy for your patients with the disease? 

Dr. Solin: This controversy has changed the decision-making process about when to add radiation therapy, but not about how radiation therapy is delivered. We would not offer radiation therapy to a patient with very low-risk disease. For high-risk patients, we tend to add radiation to the treatment, so the controversy changes the decision-making process. But when we add radiation therapy, a standard course of radiation therapy is prescribed. 

Defining Low-Risk Disease 

What is the definition of low-risk DCIS, and when is watchful waiting appropriate in treating women with low-risk disease? 

Dr. Hwang: We are trying to better identify what constitutes low-risk disease. The international trials designed around low-risk DCIS each define it a bit differently. In the COMET trial, we have defined low-risk disease as low- and intermediate-grade without comedo necrosis that is estrogen receptor–positive or progesterone receptor–positive and HER2-negative, if tested. 

In the future, we will have a better way of communicating risk to patients. Part of what we are doing with the COMET and related studies is to determine how women perceive risk and what amount of risk they find acceptable. Physicians always recommend treatment that gives women the lowest risk for invasive disease, regardless of what the side effects are and what a person’s risk tolerance is, but that is how we have to frame this discussion, because these patients are not going to die of their disease. They are in a risk-management situation, not a cancer-treatment situation. 

“By understanding the gene signature of the tumor, we can give each patient a greater understanding of her individual risk, which allows the patient to make a more informed treatment decision.”

— Lawrence J. Solin, MD

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We have to help women understand what their risk is now and what that risk looks like going forward. We know what the risk looks like when patients receive standard treatment, but we don’t yet know what it might look like when patients choose watchful waiting. Just as with low-risk prostate cancer 20 years ago, there will be uncertainty, but, hopefully, in 10 or 15 years, we will have a different way of managing DCIS because we will have created evidence for watchful waiting that women can consider when they are making treatment decisions. 

Dr. Partridge: For the COMET trial, we are defining low-risk DCIS by the extent of the disease, the grade of the tumor, and the presence or absence of hormone receptors, as well as the absence of higher risk features, such as comedo necrotic cancer cells. 

Dr. Solin: People have used very different definitions to describe low-risk DCIS, and there is no single uniformly accepted definition. The early iterations used clinical and pathologic characteristics, such as patient age, tumor size, grade, and tumor margins, to determine risk. Today, molecular profiles have to be considered in any discussion of low-risk disease because the molecular signatures have a substantial impact on understanding tumor biology for the individual patient.

Predicting the Development of Invasive Disease 

What is the current state of the use of gene signatures for predicting the development of invasive breast cancer in DCIS? 

Dr. Hwang: It is important to distinguish the current molecular signatures from the ones we hope to develop. The current tools are based on women who have had a lumpectomy to determine their risk of having subsequent invasive cancer. What we are trying to do in the COMET trial is to determine on the basis of just a core biopsy whether the risk is high enough to have surgery at all. Most of the women in this study who are in the active surveillance arm have not had any surgery except for a core biopsy. So we will develop a molecular signature for a slightly different purpose and if we are successful, we will be able to identify those women with DCIS who are likely to be stable for a long time. We hope to follow women in the COMET trial for at least 10 years to determine their long-term risk of having a subsequent event. 

Dr. Partridge: In the standard arm of the COMET trial, we will also document what proportion of patients have invasive cancer when their DCIS is diagnosed, so it is not only the development of DCIS, but the undetected invasive cancer that may be there as well. It is a low percentage of women, but in the lower-risk type, the percentage is lower than in the higher-risk type, which is why the COMET trial is enrolling only women with low-risk disease. 

Dr. Solin: The use of gene signatures, such as the Oncotype DX DCIS Score, has added to our understanding of the underlying biology of DCIS. The Oncotype DX Breast DCIS Score and other molecular signature tools help us identify underlying tumor biology that may not be apparent using traditional clinical and pathologic characteristics of the tumor. By understanding the gene signature of the tumor, we can give each patient a greater understanding of her individual risk, which allows the patient to make a more informed treatment decision. 

How the COMET Trial May Reduce Overtreatment 

Please talk about how the results from the COMET trial may reduce overtreatment of DCIS. 

Dr. Hwang: First, it will get people thinking and talking about DCIS and how to approach it, what to call it, and how to deal with it. Second, it will create evidence around the approach of watchful waiting for stage 0 breast cancer and provide a level of comfort around offering careful monitoring to patients who we believe have low-risk disease, much as is currently done for early-stage prostate cancer. The COMET trial will provide familiarity with what a surveillance protocol looks like and, hopefully, also provide evidence for what surveillance should look like in the future as we get more data on outcomes for patients with DCIS. 

Ultimately, we want to provide patients better evidence about what to expect when they choose active surveillance and compare that evidence with what happens when women receive routine treatment. We will compare many different types of outcomes, of course including oncologic outcomes, but also quality-of-life outcomes, so women can make informed decisions that are most in line with their risk tolerance, their tolerance for treatment side effects, and their tolerance for uncertainty. Women will then be able to put this information into a framework to make a decision that is not just driven by recurrence statistics. 

Dr. Partridge: Our hypothesis is that women in the active surveillance arm of the study will not have an inferior outcome and will have a low likelihood of developing invasive breast cancer in the short-term follow-up at 2 and 5 years compared with the women in the study who undergo standard treatment. Women in the active surveillance arm will be closely monitored for disease progression and have mammograms every 6 months. 

For some women, more monitoring is not an appealing choice because it is not convenient, and some women don’t want to risk invasive cancer because DCIS can essentially be cured for many with surgery. So that is the debate we hope to clarify with the COMET trial: Is it better to treat DCIS or leave it alone? And for whom does this strategy make sense, both from the disease type and patient preference perspective? 

Changing the Treatment Paradigm for DCIS 

How may the results from the COMET trial change how physicians counsel their patients with DCIS and other low-risk cancers about how best to treat these cancers? 

Dr. Hwang: The COMET trial will help define whether some women with DCIS have such a low risk for cancer that they may be treated with biopsy and observation alone—similar to our approach to atypical ductal hyperplasia and LCIS. This would allow patients and their providers an option to de-escalate treatment for some cases of DCIS and to balance the effects of treatment compared with surveillance for an individual patient. 

Dr. Partridge: We all have experienced patients in our practices who have been destroyed by their breast surgery, especially mastectomy. It’s a rare occurrence, but it happens, and the result is some women are living in chronic pain and with a cosmetic defect. The issues are not as profound with lumpectomy, although there are data suggesting people who have a lumpectomy have a lot of ongoing discomfort, too. 

Studying whether to immediately treat patients with DCIS or monitor them closely with active surveillance is a worthwhile endeavor. First and foremost, we want to know is watchful waiting a safe approach for some women? Once we know that answer, we can apply it to real-world patient settings, but first things first. 

Dr. Solin: The data from the COMET trial and the two European trials will potentially be valuable in clinical practice. The results from these trials will give us further evidence about when it is safe to de-escalate therapy and which patients will benefit most from active surveillance. These results will tell us when core biopsy alone may be appropriate treatment. This will give us another tool to further tailor and personalize treatment, which will be a huge advantage for our patients. 

DISCLOSURE: Drs. Hwang and Partridge reported no conflicts of interest. Dr. Solin is a nonpaid member of the advisory board for Genomic Health, Inc. 

REFERENCE 

1. American Cancer Society: Breast Cancer Facts & Figures 2017-2018. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed February 27, 2018.