The New Frontiers of Breast Cancer

Three breast cancer experts discuss how precision medicine is leading to less aggressive treatment and better outcomes for patients with the disease.



Laura J. Esserman, MD, MBA

Julie R. Gralow, MD

Marisa C. Weiss, MD

The most fundamental change in our understanding of breast cancer is that biology trumps stage, which to me means that size isn’t necessarily as important as the biology of the tumor.… There are indolent cancers or even tumors that should not be called cancers and that may not need immediate treatment.

—Laura J. Esserman, MD, MBA
We are paying more attention to overtreatment. With respect to these low-grade, early-stage tumors in older patients, based on age, comorbidities, and life expectancy, there is a group we should not be screening with mammography.

—Julie R. Gralow, MD
In general, metastatic disease requires continuous treatment, and it is important to redefine the extent and nature of the recurrent and progressive disease. We can’t assume that the recurring disease is the same as the original cancer.

—Marisa C. Weiss, MD

A seismic shift is underway in screening and treatment approaches for breast cancer. These changes are being fueled by studies showing that mammography in younger women may do more harm than good and that advances in genomic testing and a better understanding of the biology of breast cancers may enable clinicians to prescribe more precise care for their patients, sparing them needless overtreatment. Six years after the U.S. Preventive Services Task Force (USPSTF) recommended that women start mammography screening at age 50 instead of age 40,1 the American Cancer Society (ASC) announced that it, too, was changing its recommendations2 for the start and frequency of mammography for women at average risk for breast cancer.

The new recommendations call for average-risk women to begin annual screening at age 45, instead of age 40, and that the tests be done less ­frequently—every 2 years rather than yearly for women 55 and older. The ACS is also recommending ending clinical breast examinations as well as breast self-examinations. And while the changes in ACS policy did not stir up the same level of national uproar as the USPSTF’s did in 2009, they are still raising concern among some oncologists, advocacy groups, and patients who say that early detection improves survival.

When to screen women for breast cancer and how aggressively to treat them when cancers are found—especially when the cancers are preinvasive and may never advance to become life-threatening (eg, ductal carcinoma in situ [DCIS])—are issues at the center of a new debate among oncologists on how best to approach the disease.

To learn what new research is showing on the most effective screening and treatment options for women with early- and late-stage breast cancer and how the findings are impacting clinical care, The ASCO Post held a roundtable discussion with three leaders in the field: Laura J. Esserman, MD, MBA, Director of the Carol Franc Buck Breast Cancer Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Julie R. Gralow, MD, Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington School of Medicine and Director of Breast Medical Oncology at Seattle Cancer Care Alliance; and Marisa C. Weiss, MD, Director of Breast Radiation Oncology at Lankenau Medical Center in Philadelphia and Founder and Chief Medical Officer of Breastcancer.org.

Individualizing Care

Advances in genomics and a greater understanding of the biology of different types of breast cancer are changing treatment strategies for the disease. What are you learning about the prevention, detection, diagnosis, and treatment of breast cancer; how is the treatment for breast cancer becoming more individualized; and what might the change mean for overall outcome and survival?

Dr. Esserman: The most fundamental change in our understanding of breast cancer is that biology trumps stage, which to me means that size isn’t necessarily as important as the biology of the tumor. I have been very vocal about explaining that there are indolent cancers or even tumors that should not be called cancers—not just in breast cancer but across all cancer types—that may not need immediate treatment. Previously, we did not understand this nuance; you do not often see the manifestation of these indolent cancers until you screen for them. Redefining “what is cancer” in 2016 is an important scientific opportunity.

If you screen for cancer, more cancers with a low-risk biology are going to surface. We think that probably one-third of cancers fall into the ultra–low-risk or indolent category. We have to adopt screening and prevention strategies recognizing that these indolent lesions or less aggressive cancers exist and that they do not have to be aggressively treated. This is what personalizing therapy for patients is all about.

If we recognize that there are indolent cancers, less aggressive treatment upfront is probably sufficient, especially for women with shortened life spans. And, certainly, we do not want to find precursors to those indolent cancers, because early intervention will just increase the morbidity rate (eg, low-grade DCIS).

Dr. Gralow: We have known for some time basic ways of stratifying breast cancer—most importantly, by whether the cancer expresses the estrogen receptor or overexpresses HER2—and how to treat breast cancer based on those stratifications. With genomic testing and a better understanding of the biology of breast cancer, we are getting beyond estrogen receptor and HER2 disease and understand that even a subtype of breast cancer, such as triple-negative disease, encompasses multiple subtypes.

We have a better understanding of what the drivers of these subsets are and what does or does not work, but we have not converted this information to the clinic yet. The more we look at these subsets, the more we understand that every breast cancer is unique.

Dr. Weiss: I agree: There is no one-size-fits-all approach to treating breast cancer. Each patient is unique and wants to take full advantage of the best relevant medical advances from multiple fronts. There is a better understanding of the cancer itself and how to determine a tailored, customized approach for each patient. The goal is to give the best treatment approach from the beginning—one that will provide the greatest benefit and least toxicity for each individual.

But the approach to treating breast cancer is not just about looking behind the curtain to see what is driving the disease; it is about understanding each patient’s unique physical and emotional situation as well, including her overall health and goals. Women want a holistic approach to their personalized care.

Achieving More by Doing Less

Are advances being made in your ability to better determine who will benefit most from a specific treatment, thereby eliminating unnecessary aggressive treatment and toxicity? In other words, is it possible to do less and still achieve a good outcome?

Dr. Esserman: We have found an ultra–low-risk threshold that we think defines indolent cancers, and I think that is where the opportunity is to feel comfortable giving less aggressive therapy. There is also the opportunity to understand who has the higher-risk type of lesions. Oftentimes, surgeons are the first physicians to see newly diagnosed patients, and when there is uncertainty about whether the cancer is significant or consequential, surgery is sequenced first.

When it is clear that the cancer is triple-negative, HER2-positive, or has spread to the lymph nodes, our concern is that the patient will die of systemic disease, so systemic therapy is most important in those situations, and understanding the impact of those systemic therapies is critical.

My recommendation is that we flip the order of therapy. I am a big proponent of neoadjuvant therapy, whether it is chemotherapy or hormonal therapy. We started the I-SPY breast cancer trial to learn about tumor biomarkers and how to match combinations of drugs to provide the greatest benefit and least toxic side effects and to accelerate the pace of finding the right drug for the right patient. The next phase of that trial will investigate how to determine the right sequence of agents if a patient is not responding to treatment. When you have a patient with aggressive cancer, the big challenge is to prevent her death by accurately figuring out how to get the most effective therapy for her cancer upfront.

Next-generation gene sequencing of the host is making it possible to identify people who clearly have a high risk of getting breast cancer, and we now know that there are genes associated with early-onset breast cancer. These are the people who should be given preventive interventions and intensive screenings at appropriate intervals.

To give us the knowledge to determine a personalized approach to breast cancer screening for women, we have launched the WISDOM study (Women Informed to Screen Depending on Measures of Risk), which is enrolling 100,000 women 40 to 80 years old, to test a personalized schedule of screening based on each woman’s individual risk for breast cancer.

We are going to let the science drive screening frequency. For women with very low risk for disease, we should screen them less often, and for women at high risk for disease, we should screen them more often. That is what personalized medicine is all about.

Dr. Gralow: In 2000, the National Institutes of Health held a Consensus Development Conference3 to review questions regarding adjuvant treatment of breast cancer. The participants could not determine who would benefit most from chemotherapy and concluded that everyone should, therefore, get the therapy. We all knew that conclusion was wrong, but we could not change the strategy because we could not figure out who would and would not benefit from chemotherapy.

Now we have profiling assays such as the Oncotype DX and MammaPrint genomic tests among others, to tell us which patients have good- or bad-risk cancers and which cancers respond more to chemotherapy or endocrine therapy, and we are absolutely giving less chemotherapy as a result.

We are also learning more about defining populations of patients who do not benefit from adjuvant radiation after lumpectomy to ward off recurrence or who do not benefit from whole-breast irradiation and can have accelerated partial-breast irradiation instead. So “less is more” is a real trend in breast cancer treatment.

Dr. Weiss: Yes, we are absolutely making advances in our knowledge of personalizing treatment for patients. Prior to treatment is selection. It is critical to take time upfront to fully define the extent and nature of the disease. In appropriate patients, it is also important to identify any potential inherited predisposition like BRCA1 or BRCA2 genetic mutations. In the setting of advanced disease, genetic testing of the cancer itself may reveal important clues for the role of targeted therapies against genetic drivers. Of course, it is also critical to understand the patient’s preferences and style of making decisions, as well as to assess her overall health and expected lifespan.

There are also genetic changes that tell us how one form of treatment may be more problematic than another. For example, patients with the TP53 gene abnormality may have more issues with radiation therapy than patients without that mutation, and radiation therapy should be avoided in this group if possible.

Regarding overdiagnosis, I believe a missed or delayed diagnosis is much more harmful than a false-positive mammography screening. And I worry about using outdated historical analog mammography data to make futuristic guidelines for modern-day mammography, since medicine has marched forward and we have much better tools with which to make more accurate diagnoses and avoid overtreatment.

Are women being overtreated? Yes, there is overdiagnosis and there is overtreatment since there are breast cancers that may never be life-threatening. But right now we do not know exactly which cancers will remain indolent and which ones will become aggressive. And the cancer needs to be removed in order to be fully defined and staged. For example, a core biopsy of a mass that shows just grade 1 DCIS may be a sampling error. The mass needs to be removed to be sure that there is no significant noninvasive or invasive disease present. Moreover, our data on the natural history of both DCIS and invasive breast cancer are from after lumpectomy with essentially clear margins.

After a diagnosis, we now have the Oncotype DX test for DCIS and hormone receptor–positive early-stage invasive disease to help us make treatment choices, and there are more accurate tests in the pipeline. But right now, it is still a gamble to predict who does or does not need treatment or how aggressive treatment should be. Until we have those more discriminating tests, we will probably continue to overtreat patients to reduce the risk of recurrence and treat more patients than we need to.

Watch and Wait

When is active surveillance in breast cancer appropriate?

Dr. Esserman: We are creating a DCIS registry across the five University of California medical centers to offer women with DCIS options, including active surveillance, chemoprevention, or surgery, and track their outcomes over decades. I do not believe that low-grade DCIS should be a target for screening, because we have not demonstrated that we are improving outcomes by going after it, and we have not lowered the rates of invasive cancer.

I am a member of the Consortium for Molecular Characterization of Screen-Detected Lesions,4 and we are working to better define what I call IDLE (indolent lesion of epithelial origin) conditions vs aggressive cancers. We did not have the opportunity to understand and classify cancers differently in the past, but now that we are screening cancers and finding all the low-risk disease, we have the opportunity to consider that some of these cancers can be reclassified and called something else. This is just as essential as finding better ways to treat the aggressive cancers, because all of our interventions have complications, both psychological and physical. Personalized medicine does not just mean doing more for some; it also means doing less for others, and that is just as important and deserves as much attention as finding new treatments.

Dr. Gralow: In breast cancer, the idea of active surveillance is a new concept. In cases of in situ disease, such as DCIS, there is undoubtedly a subset that will never evolve to invasive cancer, where watching it and not giving aggressive treatment is reasonable. Currently, however, I don’t think we are great at picking out which DCIS will go on over time to have another mutation and turn into invasive disease and which cases will not.

If there is just a millimeter of DCIS, and it is low-grade and quiet, can you leave it and watch it? Yes, probably. But that is not what we usually find with DCIS. Is there any invasive disease we can just watch? I would say there are some low-risk, early-stage breast cancers, particularly in older women, where we can either leave it in place or just perform surgery (but not give radiation), and watch to see if the cancer grows.

We are paying more attention to overtreatment. With respect to these low-grade, early-stage tumors in older patients, based on age, comorbidities, and life expectancy, there is a group we should not be screening with mammography.

 

How do we define DCIS vs invasive breast cancer? That is what this whole question of the appropriateness of active surveillance is all about. Do we really want to be finding some of these early, nonaggressive tumors? We probably do not, but then how do we make sure that we find the more aggressive cancers that will impact a woman’s survival?

Dr. Weiss: We already have a number of powerful tests that help us select people who need to be treated and those who do not. Those tests are getting better and smarter. My practice approach is to make sure that each woman gets the best customized treatment possible, whatever is most effective at reducing her risk of recurrence, and to avoid or minimize any associated side effects. Along the way, it is critical to offer the right medical expertise and support at the right time so the patient can make the best decisions possible with her doctor, which is exactly the mission of my organization, Breastcancer.org.

We are getting smarter about figuring out the best treatments, but we do not yet know how to predict exactly how a particular cancer will behave, and we do not want to miss the opportunity to treat a patient for early-stage disease with reasonable and effective therapy.

Treating Metastatic Cancer

How are treatment strategies changing for metastatic disease?

Dr. Esserman: We are investigating how we can accelerate the prevention of metastatic disease and test new agents earlier in the disease course by testing new agents first in the neoadjuvant setting in the I-SPY 2 trial. Every year, we see one or two new treatments getting U.S. Food and Drug Administration approval for metastatic breast cancer. The Breast Cancer Research Foundation (bcrfcure.org) is putting a huge international effort into characterizing metastatic breast cancer to determine how to sequence and organize more effective therapies. I think we can look forward to a time when metastatic breast cancer becomes much more of a chronic disease.

Dr. Gralow: When I started my oncology fellowship in 1992, we prescribed a lot of chemotherapy and had just a handful of endocrine therapies in our treatment arsenal. Now, we have many more endocrine therapies and new categories of targeted therapies that have been designed to overcome resistance to endocrine therapies.

For the majority of patients with metastatic disease whose tumors express estrogen receptor, we have six lines of nonchemotherapy approaches that can give them years and sometimes decades without ever having chemotherapy. But we aren’t curing these women, and we need to do better, especially for women with triple-negative breast cancer.

About 15% to 20% of metastatic breast cancers are triple-negative, and we have not made huge gains in treating these women. This is a group of patients who could benefit from genomic profiling and enrollment in studies of targeted agents that match their tumor profile. For patients with estrogen receptor–positive and HER2-positive metastatic disease, we have a wide variety of drugs that are prolonging survival and that have a lot less toxicity than classic chemotherapy drugs. There are some very innovative trials looking at immunotherapies and PARP inhibitors.

Dr. Weiss: In general, metastatic disease requires continuous treatment, and it is important to redefine the extent and nature of the recurrent and progressive disease. We can’t assume that the recurring disease is the same as the original cancer. It can be very helpful to biopsy the tumor to understand the type of cancer that has recurred, because it may have altered in some way, and then we can select the most effective treatment with the fewest side effects.

Looking Ahead

What advances do you expect to see over the next 5 to 10 years in the screening and treatment of breast cancer? Will there be more effective screening methods and diagnostic tools over the next decade?

Dr. Esserman: Yes, there will be more effective screening and diagnostic tools, and I think we will be able to make a lot of progress in this disease. We will start to understand and focus on how to better identify people at risk for consequential cancers. We will probably have blood tests that identify people at risk for breast cancer, and understanding the underlying risk factors of various populations will drive a lot of the innovation. The more we can narrow down the population vulnerable to the highest-risk cancers, the better we will be able to add new tools and technologies and study preventive approaches in these high-risk populations.

We will successfully treat HER2-positive breast cancer with less-toxic combinations of targeted therapies, and I hope that will be true for triple-negative and high-risk hormone-positive breast cancers as well.

My philosophy from the beginning has been based on a precision medicine approach—that is, the art of tailoring treatment to the cancer biology, patient preference, and clinical performance. You cannot force patients to do what they do not want to do, which is how I wound up not treating some patients with low-grade DCIS. They said to me, “I’m not convinced by this treatment, and I don’t want to have drastic interventions,” and they are fine 10 years later.

Even among people who are at increased risk for cancer and breast cancer death, we have to resist the urge to be frightened and prescribe them everything. We need to know what will work to reduce that risk—and we need to find better alternatives that are less morbid. If you never try an alternative approach, you will never learn whether different approaches are successful.

Dr. Gralow: For general screening for a first breast cancer, we are at the point where we are catching a lot of lesions we don’t necessarily want to catch. What we really want are good tools that find invasive cancers early.

I think three-dimensional tomography is very promising compared to standard digital mammography, and researchers are working on noncontrast rapid breast magnetic resonance mammography, which will create high-quality images of the breasts and have better sensitivity and specificity for the detection of breast cancer. We are also looking at automated breast ultrasound as another screening tool, especially for women with very dense breasts.

In terms of diagnostic tools, we are looking at different kinds of blood tests, or liquid biopsies, that can find single cells or circulating cell-free DNA, which will detect cancer both at initial diagnosis and at recurrence. These blood assays can also allow us to do genomic profiling of the tumor. Then we have to prove that knowing there is a little bit of cancer and acting on it sooner makes a difference in survival, because that would be the next step.

As far as more effective treatment, as I mentioned earlier, I do think a better understanding of the genetic and molecular changes that lead to each cancer is going to lead to much more specific treatments for each patient, and that will lead to better outcomes. We will have more successes and some nonsuccesses, too, but we learn from it all.

Dr. Weiss: I agree. Medicine is marching forward very quickly, and we are definitely getting better at determining risk factors and in screening and treating breast cancer, so I’m very optimistic that we will be able to do a better job in the prevention, early detection, treatment, and surveillance of women at high risk of getting the disease.

We know a lot of the risk factors for breast cancer, including obesity, lack of physical activity, and alcohol consumption, and we have to do a better job of educating the public about these risk factors. If women at age 50 were to start making healthy lifestyle choices and sustain them over time, they could lower their incidence of breast cancer by 50%. And if girls lead healthy lives starting at age 2, they could lower their lifetime risk for breast cancer by 70%. Breast cancer is a serious problem, but there is a lot we can do to reduce individual risk.

Just because the American Cancer Society’s mammography guidelines call for screening to begin at age 45 and then every other year at age 55 does not mean that breast cancer risk starts at that point. There are a lot of women who think that breast cancer risk starts when mammography begins, and that is not true. That misconception is a barrier to making progress on prevention and risk reduction. ■

Disclosure: Dr. Esserman reported no potential conflicts of interest. Dr. Gralow has received research funding from Roche/Genentech. Dr. Weiss is Founder and Chief Medical Officer of Breastcancer.org.

References

1. U.S. Preventive Services Task Force: Breast cancer screening, November 2009. Available at www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-screening. Accessed January 10, 2016.

2. American Cancer Society recommendations for early breast cancer detection in women without breast symptoms. Available at www.cancer.org/cancer/breastcancer/moreinformation/breastcancerearlydetection/breast-cancer-early-detection-acs-recs. Accessed January 10, 2016.

3. Abrams JS: Adjuvant therapy for breast cancer: Results from the USA consensus conference. Breast Cancer 8:298-304, 2001.

4. National Cancer Institute Division of Cancer Prevention: Consortium for Molecular Characterization of Screen-Detected Lesions created: Eight grants awarded. Available at http://prevention.cancer.gov/news-and-events/news/consortium-molecular. Accessed January 10, 2016.



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