ctDNA Testing 'Could Help Prevent Breast Cancer Relapses'

Liam Davenport

December 18, 2017

SAN ANTONIO — Regular testing in women with metastatic breast cancer by using multiple assays for circulating tumor DNA (ctDNA) could help to prevent relapses, says an expert.

In a lecture given here at the San Antonio Breast Cancer Symposium (SABCS) 2017, Nicholas C. Turner, PhD, Institute of Cancer Research and Royal Marsden, London, United Kingdom, explained that ctDNA is shed during cancer cell turnover. This ctDNA can be picked up in the blood, giving rise to the nickname "liquid biopsy."

Dr Nicholas C. Turner

Such testing for ctDNA can identify targetable mutations associated with metastatic breast cancer up to 8 months before relapse, he noted.

Now, he and his colleagues are conducting a series of studies to determine whether that knowledge can be used to guide treatment and prevent relapse, both through the use of treatments aimed directly at the specific mutation and using more general therapies designed to boost the body's own immune system.

Dr Turner gave his talk after he was presented with the American Association for Cancer Research Outstanding Investigator Award for Breast Cancer Research, funded by Susan G. Komen, in recognition of his pioneering work in the field.

He began his talk by pointing out that it has been known for several years that breast cancer has a wide diversity of mutations present.

However, although some mutations, such as PIK3CA and p53, and HER2 amplification are common, "many other mutations are only present at very low levels in breast cancer, although, in those individuals, they may be key to their treatment," Dr Turner noted.

An illustrative example is that of fibroblast growth factor (FGF) receptor (FGFR) amplification. One study showed that while FGFR1 amplification is present in approximately 8% of breast cancers, it is associated with a poor prognosis, especially in endocrine receptor–positive cancers.

Researchers at Dr Turner's institute therefore conducted a clinical trial in which they screened 341 breast and gastric cancers for FGFR amplification at baseline, identifying 17 that could be treated with an FGF4 inhibitor, based on presence of high levels of FGFR in their cancers.

"In some of these patients, we saw really quite substantial responses to therapy...that were very durable," he said.

 "But this was actually quite a sobering result for us," he commented, "because high-level amplification of the FGF receptors is really quite rare in breast cancer, and what this would mean is we'd have to screen over 100 patients to identify just a single patient who could potentially respond in the clinic."

Alongside that, many studies have shown that the genetic events occurring in metastatic breast cancer differ from those seen in the primary tumor. For example, estrogen receptor mutations are very rare in primary breast cancer but are enriched in metastatic breast cancer, as a mechanism of resistance to prior aromatase inhibitor therapy.

This "reveals the challenge," Dr Turner commented. There are multiple targetable genetic drivers in breast cancer, but many of them are, individually speaking, very rare and the drivers may be different in metastatic cancer, potentially because of prior treatment.

The additional issue is that "biopsies of recurrent cancer are challenging for our patients, and they're certainly rarely repeated through the metastatic course to survey what's happening with the cancer as we treat it."

Dr Turner and colleagues therefore became interested in liquid biopsies of ctDNA, which is detectable in over 90% of patients with metastatic breast cancer, albeit at very low levels, thus requiring specific and sensitive assays.

To determine whether these ctDNA assays could be used to guide therapy, Dr Turner and colleagues looked at data from the SoFEA trial, which randomly assigned 723 women with advanced hormone receptor–positive breast cancer to second-line endocrine therapy with exemestane or fulvestrant.

The two treatments had a similar outcome across the whole patient population. However, the analysis by Dr Turner's team revealed that 39.1% of women going onto the study had biopsy-detectable estrogen receptor mutations detectable in their cancer with biopsies.

In these patients, "exemestane was a relatively poor treatment, and patients did better when treated with fulvestrant."

This, Dr Turner said, demonstrates that "potentially, we can use liquid biopsies to guide treatment and work out what is the most effective treatment option for…second-line endocrine therapy".

The team are therefore now conducting plasmaMATCH, in which 1000 patients with advanced breast cancer are screened with ctDNA assays to find mutations in their cancer and then matched with therapies that target those mutations.

"One of the key questions that we want to address in this study is: Can we use this approach to identify those very rare, targetable mutations as a way of identifying patients for clinical trials?" Dr Turner commented. It is "already becoming clear that we can use this approach to identify some of these rare variants and guide treatment."

He continued that the "really unique" aspect of liquid biopsies is that multiple blood samples can be taken throughout treatment to monitor what is happening in the cancer.

In a study of 39 patients treated with first-line aromatase inhibitors, for example, the researchers detected endocrine receptor mutations in 56% of the patients an average of 6.7 months before they progressed.

"So we can get quite a long warning that the tumor is developing resistance with estrogen receptor mutations," Dr Turner noted.

Some women, however, can develop up to eight different mutations as they progress. This is due to subclonal resistance, in which individual metastases develop different estrogen receptor mutations in response to therapy.

"This is both exciting and pretty daunting," Dr Turner said. "It's exciting because, using liquid biopsies, we can monitor what's happened in that patient's cancer to cause her to become resistant to treatment, and potentially use that to guide the next best therapy for her.

"But it's also daunting because, in an individual patient, you can often find multiple different mutations that show individual metastases have developed different mechanisms of resistance. That is, of course, a substantial challenge for treating that patient with subsequent therapy."

Approach That "Cuts Across" Genetic Diversity

One approach to that subclonal heterogeneity is to identify a common phenotype that  potentially "cuts across" the genetic diversity "as a completely distinct and different way of treating the cancer."

An example is the use of cyclin-dependent kinase (CDK) 4/6 inhibitors, he said.

Indeed, Dr Turner led the PALOMA3 trial, which led to CDK4/6 inhibitors now becoming a standard of care due to palbociclib substantially improving progression-free survival.

Crucially, liquid biopsies showed that, to a certain extent, CDK4/6 inhibitors can cut across the genetic diversity, Dr Turner noted.

However, unpublished data from PALOMA3 on paired ctDNA sequencing showed that some mutations were present only at baseline, while others were present only in the progression sample. This could potentially drive CDK4/6 inhibitor resistance.

To use this concept to determine whether patients have been cured by therapy or not, the team recruited 55 patients due to receive standard neoadjuvant chemotherapy followed by surgery.

They took a biopsy specimen from the original breast cancer and then compared that with follow-up ctDNA samples once the patient had completed treatment.

Baseline level mutations were "not particularly predictive" of prognosis, Dr Turner said.

In contrast, every patient who had mutations on ctDNA in the adjuvant setting "regrettably then went on to relapse, with a lead time of about 8 months between detecting the circulating tumor DNA and then the patient going on to relapse."

Concluding his talk, Dr Turner said that his team has built on these data by designing the cTRAK trial, which seeks to answer the question: "Can we use these circulating tumor DNA residual disease tests to guide further adjuvant treatment?"

They will recruit 150 patients with triple-negative breast cancer who have finished their treatment and screen them for ctDNA in their first year of follow-up.

Patients in whom ctDNA has been detected will then be randomly assigned to be followed by observation (with continuation of standard follow-up) or intervention with the programmed death ligand 1 antibody pembrolizumab (Keytruda, Merck) "to see if we can stimulate the immune system to potentially clear the residual disease."

Dr Turner has received consulting fees from Roche, Novartis, Pfizer, AstraZeneca, Tesaro, and Synthon. He has also carried out contracted research with Pfizer, Roche, Merck, Clovis, and Novartis.

San Antonio Breast Cancer Symposium (SABCS) 2017. Tackling Breast Cancer Diversity. Presented December 8, 2017. No abstract 

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