'You Don't Always Need to Do More': De-escalating Breast Cancer Therapy

Liam Davenport


March 16, 2018

Imagine you have been given the devastating news that you have breast cancer.

Imagine, then, your physician telling you that after surgery, instead of the dreaded cycle after cycle of chemotherapy and decades of pills to reduce the risk for recurrence, you can have just one course of therapy targeted to your specific type of breast cancer. And then, if all goes well, nothing more.

That might sound fanciful, considering that the traditional approach to breast cancer treatment has been to add more and more therapies to ever-more complex regimens so as to leave no stone unturned in tackling this life-threatening disease.

However, that is exactly the sort of conversation that patients with breast cancer could soon be having with their physicians, owing to a sea change in disease management that is currently taking place. This change is being driven by a better understanding of the complex biology of breast cancer; the development of targeted therapies; and, thanks to the tireless work of advocacy groups, the growing realization that patients' quality of life needs to be prioritized if they are to survive well with the disease.

The result is something that would have been inconceivable 20 or 30 years ago but is now becoming a reality: a novel approach to treatment known as "therapy de-escalation."

We are all aware that we overtreat too many patients.

What Is De-escalation?

"Therapy de-escalation" could simply be defined as the reduction of patient exposure to therapy and its adverse effects. But what does that mean in practice, and how can it be achieved?

One route is to reduce the duration of a proven therapy to the shortest period that still offers the maximum benefit.

Another is to make more appropriate treatment choices—by, for example, giving only medications that are known to improve outcomes, or withholding drugs that offer no additional benefit. This could include slimming down chemotherapy regimens to reduce the number of medications given at each cycle; giving just one adjuvant therapy rather than two when the second does not further improve outcomes; or even leaving out chemotherapy altogether in patients who will respond well to targeted therapy.

As Carlos Arteaga, MD, director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, put it, "We are all aware that we overtreat too many patients."

He pointed out that previously, the addition of further therapies to existing regimens yielded substantial benefits to patients, even if it meant an increased risk for adverse effects. "For example, when you look at the effect of adjuvant tamoxifen, adjuvant chemotherapy, the number of patients who were saved by those interventions were significant," Dr Arteaga said.

However, the picture is different when looking at the results of, say, the more recent APHINITY trial, presented at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting and published in the New England Journal of Medicine.[1]

As reported by Medscape, this study of over 4800 patients with early HER2-positive breast cancer showed that the addition of pertuzumab (Perjeta®) to standard trastuzumab (Herceptin®) offered only modest improvements in outcomes, at the expense of a notable increase in adverse events.

Dr Arteaga noted, "There's maybe one or two patients that benefited from that very expensive approach." He added, "If you deploy the dialed-up therapy to everybody, for one thing the world cannot afford it, and the other thing is it's unnecessary for the overwhelming majority of patients. Thus, the need for 'not escalation,' or de-escalation."

However, de-escalation takes many forms, and does not only mean simply changing systemic/medical therapies.

For example, Lisa Newman, MD, director of the Breast Oncology Program at the Henry Ford Health System in Detroit, Michigan, highlighted that there have been "huge strides in de-escalating the locoregional management of breast cancer." She noted that axillary lymph node dissection, which was routinely performed in the past as a staging procedure for every invasive breast cancer case, "has now been largely replaced by the much less morbid sentinel lymph node biopsy, and far fewer patients therefore have to face the risk for lymphedema."

Moreover, hypofractionated radiation schedules allow lumpectomy patients to receive their treatment in just 3 weeks rather than the traditional 5-6 weeks, thus reducing "the inconvenience and time commitment of breast radiation therapy."

What Are the Advantages?

The benefits of de-escalating or not escalating therapy are manifold. They include not only improving patients' lives by reducing adverse drug effects but also in helping to reduce the burden of the disease and its associated costs.

Dr Newman described the reduced toxicity and improved effectiveness with such an approach as "a win/win for the breast cancer community."

She added, "Many treatment-related toxicities are chronic conditions that have a long-term impact on overall well-being and professional productivity. These adverse effects are not only significant to the individual patient and her family, but they incur substantial costs for our entire society as well."

Ian Krop, MD, PhD, chief of the Breast Oncology Center at Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, Massachusetts, agreed, noting that, "Even with a completely nontoxic drug, it still requires [patients] visit their oncologists, taking them away from their families and their workplace."

There's probably a psychological impact of having to say, "You're at risk for recurrence.'

He added, "I don't know how well this is studied, but there's probably a psychological impact of having to say, 'You're a person who's at risk for recurrence, and so you need to keep taking this pill.' That reminds them that they have breast cancer and that they are at risk for recurrence, whereas the sooner you stop that, one would hope that you can help them return to normal life faster."

That, of course, illustrates how the drive to rationalize breast cancer therapy and minimize its negative impacts has come from a range of different sources, including patients themselves, alongside the efforts of clinicians and researchers.

Dr Newman believes that the breast cancer community should be "thankful for the creativity, as well as the natural humanity, of the many physicians and scientists" who have helped better characterize breast cancers and develop innovative, targeted treatments.

However, she added, "We also owe a huge debt of gratitude to the breast cancer advocacy community, including survivors and their network of care providers."

"These advocates have worked tirelessly to raise awareness as well as funds for clinically relevant and meaningful breast cancer research. They also lend their powerful voices of experience to clinical trialists during the design of research projects and the review of grant applications," she said.

Dr Newman also believes that the overall steady improvement in the gender balance in medicine has "played an important role in driving the development of breast cancer treatments that prioritize survivorship, as well as quality of life," as that has brought to the fore "important perspectives related to female life experiences."

A More Nuanced Approach to Personalized Medicine

Taken together, these efforts could be seen as a natural progression—an evolution, even—of the concept of personalized medicine. However, the aim now is not to simply keep adding treatments to catch all possible disease permutations, but instead to offer a more nuanced approach, in which therapies are just as likely to be subtracted as added.

"The right combination or the right treatment does not imply always adding more; it implies being smarter about how we do things," said Dr Arteaga.

He added, "There are probably some patients with HER2-positive, estrogen receptor (ER)-positive disease who may not need chemotherapy and may need only anti-HER2 therapy and hormonal therapy."

One example is the PAMELA study, which was presented at the 2016 San Antonio Breast Cancer Symposium (SABCS) 2016 and published in Lancet Oncology.[2] This phase 2 trial examined whether dual HER2 blockade would be sufficient in patients with the HER2-enriched subtype, as measured by gene expression.

"The pathologic complete response rate was extremely high, suggesting the possibility that, in those patients, one can obviate chemotherapy," said Dr Arteaga.

However, noting that clinicians and researchers still have "homework we need to do," he said, "The question is: How do you de-escalate and in whom, knowing that the majority of patients don't need that magnitude of treatment; that that treatment is not not toxic; and that more treatment, for sure, affects quality of life?"

Fortunately, help may be at hand to identify suitable patients for therapy de-escalation, with the development of genetic tests such as Oncotype DX® (Genomic Health) and MammaPrint® (Agendia), among others.

Dr Krop, who led a recent ASCO clinical practice guideline focused update on the use of biomarkers to guide decision-making,[3] said that data on these and other "genomic predictors has helped basically validate what most of us in the field have already known for some time." In other words, "biology matters: Low-grade cancers don't tend to respond as well to chemotherapy but respond very well to hormonal therapy, whereas triple-negative breast cancers have higher recurrence rates and need more therapy."

Although the impact of cancer grade on both prognosis and the potential benefit of treatments is well characterized, Dr Krop believes that "having these genomic tools, which to a good extent provide a quantitative assessment of these things that we already see on old-school pathology...can help us select which treatments work best for which people."

That, he said, has "given us the confidence to now push the idea that we can personalize medicine and direct therapy to people who really need it and take it away from people who don't.... We don't have to use a one-size-fits-all approach, because we are not in the dark as much as we used to be in terms of what's going to happen to the patient."

How Did De-escalation Get Started?

The origins of therapy de-escalation in breast cancer do not lie in a single, pivotal event, but rather in an increasing awareness in the breast cancer community that there needed to be a change in focus.

"There's been, actually for some time, a groundswell of support for trying to figure out at least in which instances we can start de-escalating therapy, and we can de-escalate therapy safely," said Dr Krop.

We've all realized that we are overtreating a large number of people.

"Overall, women with breast cancer do fairly well and, up until relatively recently, most of our trials have been trying to further improve outcomes by adding additional treatment, and that makes sense."

He said that it is "simpler" to conduct trials in which treatments are added "in a relatively nonspecific way, and that has led to improvements in outcomes."

However, Dr Krop pointed out that "the improvements have been relatively small over the past decade or so, and I think we've all realized that we are overtreating a large number of people. But I don't know that there's been a particular moment in time in which we've said that there we've gone too far, and now we need to start backing off."

Dr Arteaga agreed, saying, "The point is that it is very clear that all these so-called breakthroughs and advances are increasingly minimally incremental. It's sort of an oxymoron here, but...some of these trials that we would call positive are really not having a terribly huge impact in a large number of patients. They have been statistically significant, by the mathematics, but a P value—a mathematical result—may not necessarily equate to a high impact on the natural history of the disease."

The achievement of optimal outcomes does not always rely on the addition of therapies.

This awareness has been driven by a better understanding of the underlying biology of the various breast cancer subtypes, which has in turn shown that the achievement of optimal outcomes does not always rely on the addition of therapies.

Matthew Goetz, MD, from the Department of Medical Oncology at the Mayo Clinic, Rochester, Minnesota, gave the example of ER-positive breast cancer, where "the move to de-escalate has been ongoing for some time."

"Back in the 1980s and 1990s, there was a series of studies that suggested that chemotherapy should be given in addition to the drug tamoxifen for early stage breast cancer," he said. "Over the past 10 years, multigene signatures were developed. Essentially, those signatures identified a group of women who had such a good prognosis that they really did not need that chemotherapy, and that chemotherapy was only adding toxicity."

A Work in Progress

Despite these advances, therapy de-escalation remains a work in progress, with a number of trials either only recently reported or still ongoing.

For example, the ABCSG-16 trial, which was presented in December at SABCS 2017, looked at whether postmenopausal women with hormone receptor–positive breast cancer who have already been on endocrine therapy for 5 years could have just 2, rather than 5, years of additional therapy with the aromatase inhibitor anastrozole (Arimidex®).

As reported by Medscape, this study of almost 3500 women showed that the 2- and 5-year regimens offered the same reduction in relapse risk, but that the shorter regimen was associated with less of an adverse effect on bone health, potentially protecting women from fractures.

Discussing the study, Dr Krop said that it underlines the "natural evolution" of breast cancer treatment. "We first do a study that shows there's a benefit to doing more and then, once we've proven that, you can start cutting back," he explained.

The NSABP B-47 study from SABCS 2017 is an example of how adding treatments is not always beneficial. The trial enrolled more than 3200 women with HER2-low breast cancer who were randomly assigned to standard adjuvant chemotherapy with or without the addition of 1 year of trastuzumab therapy.

Despite earlier signals that the drug, which targets HER2, may be beneficial in women with low expression of the protein, the study revealed no benefit in invasive disease-free survival.

"Why would you add an antibody that is expensive and that can have some toxicity?" Dr Arteaga asked, noting that he made a comment at the time that negative trials such as NSABP B-47 are "good news" for patients. "The good news is that you're avoiding a treatment that is not needed, that is costly and can be toxic, and patients know now that yes, I don't need this treatment because my tumor is not really dependent on this alteration."

SABCS 2017 also saw the presentation of data showing that taking out individual drugs from chemotherapy regimens does not necessarily reduce their effectiveness. The study, by Rashmi K. Murthy, MD, MBE, from the University of Texas MD Anderson Cancer Center in Houston, Texas, and colleagues, built on earlier research by the team presented at ASCO 2017.[4]This showed that for patients with stage II-III HER2-positive breast cancer, giving trastuzumab and pertuzumab-containing regimens yielded a higher pathologic complete response rate than giving trastuzumab alone.

As Dr Murthy pointed out, this is "to be expected, on the basis of what we know from the TRYPHAENA and NeoSphere studies."[5,6]

For the analysis presented in San Antonio,[7] they focused on the 215 patients who had received both trastuzumab and pertuzumab-containing regimens to tease out the impact of the different chemotherapy backbones used. This included 87 patients who had received anthracycline-containing chemotherapy, 90 patients who were given backbone chemotherapy that included carboplatin, and 38 patients treated with a taxane alone.

The results showed that after age, stage, hormone receptor status, grade, and menopausal status were controlled for, there was no significant difference among the three regimens in the pathologic complete response rate, although the taxane-alone and anthracycline-containing groups had a larger overall pathologic response rate.

This, the team says, suggests that there may not be "a clear efficacy benefit to receiving a neoadjuvant regimen containing carboplatin" compared with one without it, especially given that the drug was associated with higher toxicity and complication rates.

"The ideal would be to achieve a situation where we're giving the necessary therapy to achieve good outcomes but not giving more than the necessary, in an effort to avoid toxicity," Dr Murthy said. "This study adds to prior reports that question the role of carboplatin as a component of chemotherapy in HER2-positive breast cancer and the omission of carboplatin may be considered in select patients in the setting of dual anti-HER2 targeted therapy."

One investigation that could affect future treatment choices is the ongoing KATHERINE study. In this phase 3 clinical trial, patients with HER2-positive breast cancer with residual tumor in the lymph nodes after preoperative therapy are randomly assigned to receive trastuzumab or combined trastuzumab emtansine (T-DM1; Kadcyla®). The results of this trial could have an impact on adjuvant treatment in this high-risk group.

Is De-escalation Ready for the Clinic?

With all these recent and ongoing advances, how close are we to bringing therapy de-escalation into daily clinical practice?

Dr Krop sees both the better use of tumor biology to tailor therapies and shorter durations of treatment already moving into the clinic, because oncologists are "fairly receptive to these data sets that show that you don't always need to do more." He added, "The data from the ABCSG-16 trial will be implemented in terms of cutting back the years of extended adjuvant treatment for patients who fit that population."

Moreover, genomic tools, such as ONCOTYPE and MammaPrint, have been widely adopted, "and that's allowed us to cut down the amount of chemotherapy being given to hormone receptor-positive patients.... That's been a huge change," Dr Krop concluded.

Dr Newman was more circumspect, however. She said that systemic therapy "is still largely driven by the three biomarkers estrogen receptor, progesterone receptor, and HER2/neu." Although these offer "invaluable information," she believes that "we need to identify alternative biomarkers that will accurately predict benefit from novel immunotherapies. We also need to be able to better characterize triple-negative breast cancers using markers that have some clinical relevance in terms of treatment-planning."

For Dr Goetz, the whole notion of therapy de-escalation, particularly in HER2+ disease, remains a research topic. He noted that "one of the main drivers of de-escalation therapy, especially in early-stage breast cancer, has been the whole advent of neoadjuvant-based therapy."

Previously, it would take anywhere from 5 to 15 years after surgery to determine whether a drug would have an impact on long-term patient survival.

We're using early response to chemotherapy as one way to identify patients for de-escalation.

Now, especially in HER2-positive and triple-negative breast cancers, "we're treating patients in the neoadjuvant setting, and we're using that early response to chemotherapy as one way to identify patients for de-escalation," Dr Goetz said.

Dr Goetz believes that future clinical trials in this area will use the neoadjuvant setting, treating patients with de-escalated therapy comprising, for example, reduced chemotherapy with an anti-HER2–based therapy.

The response to treatment at the time of surgery could then be used to determine whether therapy is escalated or to decide whether, if the patient has had a complete response, the treatment they had before surgery was sufficient.

"I think that, really, is going to be the next set of clinical trials that are going to be developed, and some of those are already in development right now," he said.

Dr Krop added that another avenue of research will be to develop tests that can determine which patients have microscopic metastatic disease, "which is the underlying problem for recurrence." With numerous studies "looking at circulating tumor cells as way of potentially identifying those patients who are at risk," he believes that clinicians will be able to move "away from the realm of probability."

Then, Dr Krop continued, it becomes a question of saying, "Mrs Jones, we can detect that you still have some cancer cells remaining, and therefore we need to do additional treatment for you to eradicate those microscopic cells." Or "Mrs Smith, we've done the test on you; you do not have any microscopic disease, and we don't need to give you more treatment because the treatment you've already had has eradicated your cancer."

He said, "That's kind of the Holy Grail for us...and that's going to revolutionize therapy if that technology bears out."

Reflecting on the potential for therapy de-escalation in the coming years, Dr Goetz commented, "It's certainly an exciting era."

"It's not just about adding therapy and finding new therapies, but it's making sure that we are even more precise about the treatments that we know work," he continued. "If you think about oncology for the past 40 years, who would have thought that we would get to the point where we could talk about taking away some therapies? Because that's where we are."

Dr Goetz reports being on the advisory boards of Lilly, Biotheranostics, Myriad, Eisai and Biovica; and receiving research funding from Lilly and Pfizer. Dr Arteaga reports having received consulting/advisory/speaking fees from are the Komen Foundation and Radius. Dr Murthy reports having received research support paid to her institution from Genentech, Daiichi Sankyo, and Cascadian Therapeutics. Dr Newman and Dr Krop report no conflicts of interest.


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