Liquid Biopsies and Next-Generation Sequencing Advance Precision Medicine in HR+ Breast Cancer

Aditya Bardia, MD, MPH

Aditya Bardia, MD, MPH

Next-generation sequencing (NGS) and liquid biopsies are both tools that can inform oncologists’ decisions regarding treatment options for patients and move decision making increasingly toward a precision medicine approach.

With NGS, physicians are given a more complete view of the variants in a patient’s tumor, and liquid biopsies give physicians a portrait of the tumor in real-time. Both influence oncologists’ decisions between treatment options to allow the decision to be more tailored to the patient’s specific tumor characteristics.  

During the recent18th AnnualInternational Congress on the Future of Breast Cancer, hosted by Physicians’ Education Resource, Aditya Bardia, MD, MPH, commented on the use of these tools specifically for patients with hormone receptor (HR)—positive breast cancer.

Recent evidence supporting liquid biopsy especially as a prognostic tool in breast cancer comes from the SOLAR-1 trial, explained Bardia, an assistant professor at Harvard Medical School and a medical oncologist at Massachusetts General Hospital. The SOLAR-1 trial was a phase III, randomized, double-blind study of PI3K inhibition with alpelisib plus fulvestrant (Faslodex) or placebo plus fulvestrant in patients with previously treated HR-positive, HER2-negative advanced breast cancer. In an analysis, patients’PIK3CAmutation status were tested with circulating tumor DNA (ctDNA) assessments to determine the progression-free survival by mutation status. The analysis revealed that patients withPIK3CAmutations, found by liquid biopsy, had a reduced risk of progression (HR, 0.55; 95% CI, 0.39-0.79) compared with those without (HR, 0.80; 95% CI, 0.60-1.06).

This demonstrated the importance of identifyingPIK3CAmutations through liquid biopsies and NGS to identify if a patient is eligible for treatment with a PI3K inhibitor like alpelisib.

Looking towards the future, with all forms of biopsies, physicians still have to understand how to decipher which mutations are drivers and which are passengers and tumor heterogeneity to ease treatment decision making, Bardia noted.  

During an interview withTargeted Oncology, Bardia discussed the current role of both liquid biopsy and NGS in breast cancer management, improvements that are needed, and research that shows a promising future.

TARGETED ONCOLOGY: Could you discuss the current role for liquid biopsy in breast cancer?

Bardia:Liquid biopsy, essentially, refers to obtaining molecular information in the blood. In other words, getting information about the tumor status from a simple blood draw. The information that one can obtain from a liquid biopsy could range from looking at circulating tumors cell and the estrogen or HER2 receptor in the circulating tumors cells (CTCs) to looking at molecular fragments related to the cancer in the blood, such as ctDNA, to identify specific mutations that are unique to the cancer cell and are not present in the normal cell. Finally, you could also look at other fragments in the blood such as exosomes, which are fragments of tumor cells and can provide insight into the molecular machinery inside the cancer cell. 

The field of liquid biopsy has evolved from circulating tumor cells to circulating tumor DNA and now [there’s] a lot of interest in circulating exosomes.

TARGETED ONCOLOGY: How can liquid biopsy improve clinical practice for breast cancer?

Bardia:The value of liquid biopsy is [the information it provides to a physician] that could influence decision making. In the past, the value of liquid biopsy was to look at CTCs, and multiple studies had shown that presence of CTCs in the blood was a bad prognostic sign. The presence of CTCs was associated with a worse prognosis as compared [with] no CTCs.

Now with advances in technology—we can look at tumor fragments, which can tell us about mutations related to the cancer. If you have a genotype directed therapy or if you have a matched therapy against that mutation—that could potentially guide your decision making. [For example], if you profile the blood and identify a cancer related mutation, like PIK3CA, one could potentially use a PI3K inhibitor to target that mutation, which could be associated with better outcomes.

TARGETED ONCOLOGY: What research exists on the liquid biopsy and how it may improve clinical practice for breast cancer?

Bardia:For PIK3CA, we now have level 1 evidence from the SOLAR-1 trial. This was a trial looking at patients with hormone receptor—positive metastatic breast cancer. Patients who had received at least one line of endocrine therapy, were randomized to receive fulvestrant versus fulvestrant plus a PI3K inhibitor, alpelisib. The clinical trial demonstrated that, with the addition of alpelisib to fulvestrant, there was an improvement in progression-free survival (PFS). Patients who received the doublet had better PFS as compared with fulvestrant alone.

The team looked atPIK3CAmutation status by tissue as well as by blood. Both by tissue and blood, patients with PIK3CAmutant metastatic breast cancer did better with the addition of the PI3K inhibitor. In patients who had PIK3CAwild-type metastatic breast cancer, there was no improvement with the addition of alpelisib. Thus, we now have level 1 evidence that you could use liquid biopsies to identify PIK3CAmutations in a patient with metastatic hormone receptor—positive breast cancer. And if it is present, use that to guide therapy decision with the addition of a PI3K inhibitor.

TARGETED ONCOLOGY: What breast cancer patient population is most likely to benefit from liquid biopsies?

Bardia:Conceptually, it could be anyone with metastatic breast cancer. But if you talk about evidence at this time—we have evidence for hormone receptor-positive metastatic breast cancer where we could utilize liquid biopsies to identify PIK3CAmutations and consider matched therapy with the PI3K inhibitor. In a clinical setting, there could be other mutations one could look at. One could look at ESR1mutations and consider therapy directed against that, [or] look atAKTmutations as well as somaticBRCAmutations and consider therapy directed against that, in a clinical trial setting [at this time].

TARGETED ONCOLOGY: What challenges still need to be overcome before this could be incorporated into the clinic?

Bardia:The biggest challenge with liquid biopsies in terms of genotyping is similar to what we see with tissue genotyping, which is, separating the driver mutations from the passenger mutations.

Say you do a liquid biopsy with a comprehensive panel and you identify 3 different mutations. The question is, which one is the driver mutation versus a passenger mutation. That is something that can be difficult to sort out. The other challenge is tumor heterogeneity. If you have multiple mutations that are present in the blood, is one more important than the other? Could it be a false positive? Is it sub clonal and only present in one portion of the tumor? Is it present at a very low mutant allelic fraction as compared with the other, and can we use that to drive therapeutic decisions? All these factors are important considerations to optimize the signal to noise ratio.

TARGETED ONCOLOGY: What is the current role for next-generation sequencing (NGS) in breast cancer?

Bardia:NGS, either in tissue or blood, can be used to identify actionable mutations. If we can identify actionable mutations, we can potentially direct therapy against those mutations.

The NGS field started with tissue biopsies with various genotyping platforms. Now it has moved to liquid biopsies, where essentially you can get the same information but, it's much more convenient for the patient. The other advantage with the liquid biopsy over tissue-based biopsy is that you are looking at the current snapshot of the tumor. You're not looking at the archival tumor that was collected 5 or 10 years ago. The tumor could have changed from that time, but if you do a liquid biopsy looking at the status of the tumor at that time as compared to what happened in the past [you will have the current view of the tumor]. 

TARGETED ONCOLOGY: What are the challenges that oncologists still face with the use of NGS in this patient population?

Bardia:The challenges with NGS are identifying passenger versus driver mutations if there are multiple mutations present and understanding the tumor complexity before making a therapeutic decisions. As clinicians, we like answers to be black or white. But if you have a lot of information, how do you synthesize that to drive clinical decisions? These [challenges] have led to molecular tumor boards where multidisciplinary experts including oncologists, pathologists, geneticists, discuss nuances related to an individual molecular genotyping report and recommend potential therapeutic option(s) for an individual patient.

TARGETED ONCOLOGY: In your opinion, are tumor boards the best strategy for overcoming challenges with NGS?

Bardia:Tumors are complex, and it is important to understand the complexity before driving a therapeutic decision. [That may be through] a molecular tumor board, a discussion with a group of experts, or developing expertise in the field of precision medicine. I think it's important to understand the various caveats, before deciding on a therapy for an individual with metastatic disease.

TARGETED ONCOLOGY: In your opinion, looking toward the future of breast cancer, how will these tools evolve toimprove patient outcomes?

I think the approval of PI3K inhibitors forPIK3CA-mutant breast cancer, the most common mutation in hormone receptor—positive breast cancer, is just the beginning. It's the beginning of precision medicine in breast cancer, and as we have additional therapies and as we get better with our technologies, we'll see more and more precise drugs that target oncogenic drivers to improve the efficacy/toxicity index for an individual with cancer.

Bardia:The value of liquid biopsy is that you get a lot of data which will potentially provide insight in terms of what's happening with tumor evolution. If you can understand that well, you can use therapy that targets that, and that could result in improved outcomes.

Reference:

Juric D, Ciruelos E, Rubovszky G, et al. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS3-08.