Complexity 'Biggest Challenge' of Metastatic Breast Cancer

Liam Davenport


December 28, 2018

Since the turn of the century, there have been practically no survival gains for metastatic breast cancer, despite the introduction of a range of novel treatments. This sudden lack of progress is also surprising given that the past two decades of the 20th century witnessed dramatic improvements.

The cause of this apparent paradox lies in a problem that has been dogging breast cancer management ever since modern chemotherapy has come into use: tumor heterogeneity.

The result is that breast cancer continually outwits attempts to prevent metastasis and eradicate it once it occurs.

However, novel ways of examining the genetic makeup of tumors via simple blood tests have been developed, and there have been significant breakthroughs in understanding the process of metastasis. Both of these advances could point to new ways of halting the relentless advance of this disease.

No Survival Benefit With Novel Treatments

The need for novel approaches in tackling metastatic breast cancer is evident when looking at the impact of recently introduced treatments on survival versus that seen with older interventions.

Steven A. Narod, MD, Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada, explained that the chemotherapies that are "preventing the majority of deaths" today were introduced between 1980 and 1985.

He added, "Herceptin, introduced in the '90s, has had some benefit but it's only a small benefit and it's only for HER2+ patients," who represent 15% of the breast cancer population.

Furthermore, "going from tamoxifen to aromatase inhibitors...has had a measurable but very small impact on death."

Narod noted that all of the chemotherapies that have been introduced since 2000 have all been used for metastatic cancer, with the goal of prolonging life.

"If you prolong a woman's life, let's say, from a life expectancy of 2 years to 3 years, that's a benefit. It's better than nothing, but it has no impact on the number of deaths from breast cancer."

He continued, "In other words, if you have 50,000 deaths from breast cancer in 2017, and you introduce a chemotherapy that extends life by 1 year, you'll have 50,000 deaths in 2018. It's progress, but it's not measurable progress."

The Ongoing Battle Against Tumor Heterogeneity

Why do physicians seem to be hitting a brick wall with breast cancer survival when there have been breakthroughs in other forms of cancer?

"This is why we don't cure most cancers with systemic therapy," said Daniel F. Hayes, MD, past-president of ASCO and co-director of the Breast Oncology Program in the University of Michigan Comprehensive Cancer Center, Ann Arbor.

"That is that they are heterogeneous genetically and therefore phenotypically, and therefore they develop different methods of resistance to our therapies and we don't cure them."

He told Medscape that, in fact, physicians have been dealing with heterogeneity and resistance since the start of the chemotherapy era in the 1940s.

At that time, drugs were given sequentially as single agents, with patients moving on to the next once the first was exhausted. But in the 1950s, James F. Holland, Emil Freireich, and Emil Frei realized that they might get better results by combining in chemotherapies.

Moreover, Hayes said, "They made the observation that treating patients early, before they developed a metastasis, was more effective than waiting," which forms the principle of adjuvant therapy.

He continued, "That approach...was proven to be much more effective than waiting until a patient developed a metastasis, and the answer was tumor heterogeneity."

Hayes noted, "Then it was shown that combining the two concepts—combination therapy given in the adjuvant setting—is better than any therapy in the metastatic setting and better than single-agent therapy in the adjuvant setting, and that's the standard of care now."

Despite this progress, Andrew A. Davis, MD, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, believes that tumor heterogeneity remains "the biggest challenge across metastatic breast cancer and other histologies."

He told Medscape that selecting the appropriate treatments for an individual patient is complicated by two factors.

One is intratumoral heterogeneity, where there are differences in the genetics and proteomics at different sites within the tumor. This is regardless of whether the tumor is in the primary site or in metastatic sites.

The other is temporal heterogeneity, or changes in the tumor over time, which is influenced by how the patient is treated.

For example, Virginia Kaklamani, MD, leader of the Breast Cancer Program at the University of Texas Health Science Center, San Antonio, said that "estrogen receptor (ER)+ breast cancers may lose their estrogen expression, or HER2- breast cancers can become HER2+".

This is something, she pointed out, that physicians have "known for a little while, which is why we always biopsy metastatic tissue to see whether the metastatic tissue and the primary tissue are concordant."

She continued, "But what we also have figured out is that primary tissue can be heterogeneous; so, one part of it can be estrogen-positive, but it can also have an estrogen-negative clone."

Therefore, when the clinician treats the tumor with antiestrogen therapy, "one of the reasons why the treatment may not be as successful is the fact that...the estrogen-negative clone can proliferate and metastasize and, obviously, kill the patient."

Kaklamani told Medscape that one of the first ways in which this was observed was with HER2, "where you had local laboratories sampling tumors and saying this is a HER2+ breast cancer, and then, in many cases, the central laboratory was unable to confirm the HER2 positivity."

She added, "The thought was that maybe the assays were a little different, but probably the biggest reason for that was that there were different clones in the tumor that were being sampled, and then the HER2 testing was just discordant."

Another example is the use of neoadjuvant therapy for HER2+ breast cancer. When the patients underwent surgery, the residual tumor was found to be triple negative.

She said, "The question is: Is it triple negative because it lost its HER2 or is it triple negative because there was a clone that was triple negative beforehand and it just wasn't sampled when we did the biopsy initially? I think that that's probably the most likely scenario."

How Can Heterogeneity Affect Treatment?

The effect of breast cancer complexity in practice was highlighted by a recent study showing that, among women expressing low levels of HER2, adding the anti-HER2 drug trastuzumab to standard adjuvant chemotherapy does not improve invasive disease-free survival (iDFS).

While this approach seems counterintuitive, as trastuzumab would be expected to be effective only in those tumors with high HER2 expression, subgroup analyses of previous landmark studies had suggested that the treatment was equally effective in tumors with low and high expression.

However, as reported by Medscape, a randomized study involving more than 3000 patients with HER2-low breast cancer showed that adding 1 year of trastuzumab to standard adjuvant chemotherapy had no impact on 5-year iDFS.

So why was a benefit seen with trastuzumab in the earlier studies? The researchers felt that the most likely explanation was tumor heterogeneity between the locally and centrally tested samples.

An example of temporal heterogeneity in the clinic was shown by Kaklamani and colleagues,[1] who studied 30 women with hormone receptor–positive (HR+) breast cancer, all but one of whom had ER+ or progesterone receptor–positive disease at diagnosis, and subsequently developed recurrence.

"The local recurrence was more likely to be less ER+ and more HER2+ compared with the primary tumor," Kaklamani said, adding, "To me, that's the evolution of resistance. You're selecting the cells that are responding."

Hayes pointed out that mutations within tumors are, of course, random and that the cancer cells "aren't trying to develop resistance," as some mutations are neutral, while others make the tumor sensitive to therapies and others conferred resistance.

In the case of mutations for sensitivity, "we remove those clones with our therapies", but the ones that result in resistance are the ones to which "we ultimately lose our patients."

Kaklamani said, "We see this in practice because we give treatment, and some of the tumors shrink and some don't, and the question is, why? We typically don't have an answer, and I think that's the biggest issue with metastatic disease [and] why you can't eradicate it."

Joseph A. Sparano, MD, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, agreed, saying, "you're not really treating one disease."

He told Medscape, "The therapy that you have may be useful in addressing or treating a dominant clone, and when the dominant clone is impacted you get a clinical response; but at some point, the tumors almost invariably develop resistance mechanisms and then other clones emerge."

He added, "The timing by which those clones emerge, the rate at which they emerge, and the frequency of their emergence depends on the biological subtype of the tumor."

Sparano said that triple-negative tumors "develop resistance very, very rapidly, generally to cytotoxic therapies because those are the only effective therapies we have for triple-negative breast cancer. Whereas, for ER+ breast cancer, resistance may take a longer period of time to develop, and those tumors tend to be less heterogeneous."

Hayes pointed out that the aim "is to come up with better therapies, and that's the point of so-called 'precision medicine.'"

He said that "what we're trying to do is match the right drugs with the right changes in the cancer, but those really, with some exceptions, have not cured people right and left. And so what we're beginning to say, just like Holland, Freireich, and Frei did 60 years ago, is that maybe what we should be doing is combining these things against multiple mutations at the same time."

The difficulty with that, he noted, is that there are toxicities related to each drug and "we just don't know" whether this approach may be "another step forward."

However, "the whole point of this is understanding tumor heterogeneity, then being clever about how to get around it, and then doing the trials to demonstrate that that actually works."

The Limitation at the Core of Biopsies

Making progress with understanding breast cancer complexity has historically been limited by the technologies available to examine the tumor.

Davis explained that the "traditional, gold-standard way of assessing—first the tissue histology and then molecular makeup of the tumor—is getting a tissue biopsy."

"The limitation of that is that you're sampling one particular location, which could either be the primary site (for example, getting a sample from the breast if you have breast cancer) or a different site—perhaps the lung or liver, in metastatic disease," he said.

"The question remains whether that truly reflects the makeup of the entire tumor."

Kaklamani pointed out that, even within a biopsy site, there are limitations to the technique.

"Typically, people would get six cores, but that is not representative of the tumor," she said, adding that, in any case, ER and HER2 testing will be performed on all six cores.

"You pick one of them that you consider the more 'representative' of the tumor and you do that staining there, so there are possibilities for missing something. You're not testing the whole tumor, and I don't think we're ever going to be testing the whole tumor."

The reason for that boils down to several factors, Sparano noted, which include the invasiveness of taking a biopsy as well as its cost and inconvenience.

Turning to Liquid Biopsies

To get around these issues, there has been a huge interest in so-called "liquid biopsy," a relatively noninvasive test that uses blood samples to detect circulating biomarkers in the blood.

Davis said that "two common commercial applications of liquid biopsies at this point are circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs)."

He noted that, in metastatic breast cancer specifically, CTCs "have been shown to be prognostic and potentially predictive of survival, and more recently, ctDNA has been able to demonstrate the detection of tumor-resistant mutations."

Kaklamani explained that "the thought with CTCs is that the most dangerous clone is the one that's going to metastasize, and therefore the CTCs will be more representative of the 'dangerous clone.'"

However, she noted that "may or may not be the case," as this is an ongoing field of research.

Nevertheless, the potential of CTCs to affect care was shown in a recent study by Sparano and colleagues,[2] presented at the 2017 San Antonio Breast Cancer Symposium.

This involved 546 women with stage II-III breast cancer without signs of recurrence 5 or more years after diagnosis, of whom 4.9% had a positive CTC assay.

After a median of 1.6 years of follow-up, the researchers found that having a positive CTC assay result was associated with a recurrence rate per person-year of almost 20%, compared with 1% for patients with a negative assay result.

This translated into an 18-fold increased risk for recurrence with a positive CTC result on multivariate analysis, taking into account clinical covariates.

Other teams are now looking at single CTCs within the blood and testing them individually for mutations. Kaklamani stated said that it is "still unclear whether that's going to lead to any successes," especially if one CTC is different from another.

"All of that stuff is still a big area of research," she added. "We don't really have many answers, just many questions."

Tapping Into Cell-Free DNA

An area of great scientific interest is currently ctDNA, a measure of cell-free DNA, described by Hayes as "basically DNA that's floating around in the blood."

Davis added, "It doesn't last very long in the blood, with a half-life in the order of minutes to a couple of hours, so there is important research that still needs to be done in terms of understanding how ctDNA changes over time, specifically in response to treatment."

He said, "Presumably, areas that are either active or, conversely, may be dying or responding to treatment are more likely to release this DNA into the blood, so if you're using this as a biomarker of treating tumor, you want to understand what this actually means."

Hayes continued, "And the question is: Does having something abnormal in your blood mean you're very likely to be recurring or does it mean you still have dormant cells? And does having nothing in your blood mean you can safely stop taking therapy?"

Despite the ongoing open questions, several studies have suggested that ctDNA testing can be used to identify targetable mutations linked to metastatic breast cancer up to 8 months before recurrence.

As reported by Medscape, Nicholas C. Turner, PhD, Institute of Cancer Research and Royal Marsden, London, United Kingdom, and colleagues are now conducting a series of studies to ascertain whether that knowledge can be used to guide treatment and prevent relapse.

And they are not the only ones. Sparano noted that there are researchers in the United States and Canada, as well as those in Europe, who are "in the process of designing trials where we might identify patients who have occult disease by some assays and then treat the patient" once any subclinical disease has been ruled out.

One such intervention could be cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, as they are "widely used and approved in ER+ metastatic breast cancer and, perhaps more importantly, they're being widely tested in patients with early-stage breast cancer to prevent recurrence."

However, Sparano commented, "Those trials are being designed now, but I don't think we're at a point in time where we can use those assays to select patients and then change their treatment."

He added, "The information is at a stage where we need to screen large numbers of patients and then enter them into clinical trials, testing different interventions."

It is also not clear at this stage which assay—CTC or ctDNA—is more accurate and reliable in assessing breast cancer prognosis.

One study, presented by Davis and colleagues[3] at the San Antonio Breast Cancer Symposium, may shed some light on this.

Among 16 metastatic breast cancer patients from an ongoing prospective study who had undergone both CTC and ctDNA testing, they showed that there was a significant association between the number of CTCs and the total number of genomic alterations on ctDNA.

However, they found that, in HER2+ patients, ctDNA may be the more sensitive tool, as 75% of samples had detectable DNA alterations, while only 19% had detectable CTCs.

Getting to the Root of Metastatic Breast Cancer

Another avenue of research that is beginning to bear fruit is in understanding the molecular mechanisms that drive metastasis. The aim of this research is to develop metastatic biomarkers, as well as predict the potential benefit from specific therapies.

At the Albert Einstein Cancer Center in New York, John Condeelis leads the tumor microenvironment group, which, as Sparano explained, has shown that there is a specific subpopulation of tumor cells both in the primary tumor and metastatic disease that can undergo an epigenetic switch.[4]

This switch activates an isoform of a capping protein called Mena, "and when these invasive Mena isoforms are activated, they lead to invadopod extrusion or elongation, and clinging to collagen fibers."

The tumor cells then travel along the collagen fibers towards blood vessels, drawn by a hepatocyte growth factor gradient.

"This process is facilitated by macrophages that sort of travel along with the tumor cells towards the endothelial cells," Sparano said, explaining that the tumor cells secrete colony stimulating factor-1, which draws the macrophages.

The macrophages, in turn, secrete epidermal growth factor, which "stimulates the tumor cells to extrude their invadopods and they sort of form a conga line of tumor cells and macrophages."

Sparano said that once the tumor cell reaches the endothelial cells, it burrows into them adjacent to a subpopulation of macrophages that express high levels of Tie2, a tyrosine kinase receptor, and vascular endothelial growth factor (VEGF), and they together form a tumor microenvironment of metastasis (TMEM) structure.

In 2016, the Condeelis group published a paper showing that the tumor cells intravasate into the circulation only at TMEM sites.[5]

In response, Sparano has collaborated with Condeelis on developing a triple immunostain that can identify these sites, which "is essentially looking for where a Mena-expressing tumor cell, a macrophage, and an endothelial cell are in direct contact."

Their stain, which has a high level of validity on digital pathologic analysis, has now been licensed to a company.

Sparano said that this is due to them having "shown that high TMEM density in the primary tumor is associated with an increased risk for distant recurrence and gives prognostic information that's independent of the Oncotype DX recurrence score in ER+, HER2+ breast cancer."

The team is also conducting studies into blocking the release of VEGF from Tie2/VEGF-high macrophages.

This process is stimulated by angiopoietin derived from the endothelial cells, which then binds to the Tie2 receptor. The Tie2 receptor subsequently releases VEGF, and "when the VEGF binds to the endothelial cells, it causes them to contract," Sparano said.

"When they contract around a TMEM structure, the TMEM structure opens the door for other tumor cells to metastasize, and these structures may be open for as long as 20 minutes."

Sparano explained that he and his colleagues are now testing the oral kinase inhibitor rebastinib, as it has been shown to block the Tie2-mediated release of VEGF and thus block intravasation at the TMEM sites.[6]

"We've also done work in humans and in animals showing that, when you treat patients with damages the microenvironment, and results in recruitment of myelo-derived stem cells from the bone marrow and recruitment of Tie2-high macrophages," Sparano said.

Specifically, they demonstrated that although the tumors become smaller with chemotherapy,[7] "the TMEM density becomes greater, and so the notion here is that although the tumors are shrinking, they're becoming more efficient in metastasizing."

Having rebastinib can block intravasation, and the team is now conducting a first-in-human trial, in which patients with metastatic breast cancer will be randomly assigned to rebastinib with paclitaxel or eribulin, with rebastinib given either on cycle 1, day 1 of the chemotherapy or on cycle 2, day 1.

"In this way," Sparano explained, "we'll be able to isolate the effect of rebastinib."

He added that, in the 10 or so patients they've treated so far, "we're seeing evidence of clinical activity, but we're also seeing substantial reductions in circulating tumor cells."

This suggests that CTCs can be used "as an intermediate pharmacodynamic endpoint, reflecting the potential activity of this agent, and it's kind of unique because none of the other anticancer therapies that we use block metastasis."

How Will This Affect Practice?

Hayes pointed out that for a women who has finished surgery and radiation therapy, and potentially adjuvant chemotherapy, "right now, and appropriately guideline body in the world recommends any kind of special follow-up other than clinical follow-up and routine age-appropriate mammography screening."

"We don't recommend any routine blood tests or CTCs, or circulating tumor markers, or bone scans or PET scans or CT scans, if a patient is asymptomatic and the physical exam is negative."

He continued, "Maybe the time has come to readdress that in clinical trials, and that's what we hope to do in the near future."

More important, this gets to heart of what treatment in breast cancer is for.

"We're trying to make people either live longer or live better," Hayes said. "If a patient is totally asymptomatic, it's pretty hard to give her some kind of treatment that will make her feel better, because she already feels good."

The "only way" that patient could be helped is if further treatment makes her live longer or "perhaps live longer without the morbidity of cancer recurrence, but that benefit has to outweigh the morbidity of taking our therapies."

Indeed, three prospective, randomized clinical trials have already examined this question, finding that posttreatment intensive screening did not offer an overall benefit.

"However, just to be clear, those studies were performed back in the 1970s and 1980s," Hayes said. "They were performed before we had all of these new fancy diagnostics and before we had all of these new fancy therapeutics that might overcome heterogeneity."

For Kaklamani, the key to tackling metastatic breast cancer is treating the primary tumor as early as possible, ideally before it has even occurred. "To me, that's the most powerful thing," she said.

"Prevention, mostly; early detection, secondly; and better treatments in the adjuvant setting to eradicate the micrometastatic disease to begin with—I think that's where we're going to win."

"Once we get to the point where there's metastatic disease, the difficulty is just astronomical."

Daniel Hayes owns stock in InBiomotion and OncImmune and has received honoraria from Lilly and research funding from AstraZeneca (Inst), Janssen Research & Development (Inst), Lilly (Inst), Merrimack Pharmaceuticals (Prime Sponsor); Parexel Intl Corp (Direct Sponsor) (Inst), Pfizer (Inst), Puma Biotechnology (Inst). He receives royalties from licensed technology for the diagnosis and treatment of breast cancer and CTC capturing techniques and devices. He has also received expenses from Janssen Diagnostics. No other conflicts of interest declared.


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