Joseph A. Sparano, MD, discusses the potential for liquid biopsy and the ongoing challenge of improving survival for patients with metastatic breast cancer.
Joseph A. Sparano, MD
Next-generation sequencing (NGS) has the potential to improve treatment for patients with breast cancer; however, physicians first need to identify additional mutational targets and develop targeted agents to truly move the needle, according to Joseph A. Sparano, MD.
“There still are some technical challenges, but the greater challenge is the lack of targetable alterations,” he said. “That's going to be the major challenge in the field and show that patients who do have potentially targetable alterations benefit from a specific therapy.
“It's not just a matter of the assay itself,” Sparano added. “It's a matter of the assay and the limited number of drugs we have available to treat tumors associated with specific molecular alterations.”
In an interview with OncLive®, Sparano, associate director for clinical research, Albert Einstein Cancer Center, Montefiore Medical Center, discussed the potential for liquid biopsy and the ongoing challenge of improving survival for patients with metastatic disease.Sparano: There are really 3 elements to the topic. The first is the use of mutational profiling to select therapies—use of these tests as a way to predict response to specific therapies. The second component involves assays that can be used to identify subjects who could potentially benefit from therapy.
Broadly, they are broken down into assays that are tissue- or liquid-based. The assays may be predominantly prognostic or predictive, but they can also be used for other purposes like monitoring for disease or surveillance.
Last is therapeutic interventions based on this molecular testing. That is where the information is limited because we don't have many targeted therapies we can use that are based on molecular testing.A liquid biopsy is very attractive because you can avoid an invasive procedure. For patients who have deep-seated, visceral lesions, this could be an alternative. For some specific types of mutations, there have been studies showing pretty good concordance between the identification of certain types of mutations detected in blood as detected in tissue. For example, alterations of PIK3CA can identify patients who are likely to benefit from PI3K inhibitors.
There are some issues with regard to the concordance between assays. A result provided with one assay may not be concordant with the result provided by another assay. The major limitations relate to the paucity of therapeutically-targeted agents that we have that can target specific mutations. The second issue is reproducibility from assay to assay in terms of identifying mutations that are potentially predictive of response.One of the major challenges is mutational profiling of tumors. That is, biopsying tumors to look for mutations predictive of specific therapies has not shown a lot of clinical utility. The information that we get from those assays don't necessarily result in a change in treatment that benefits patients. If we're not seeing that with tumor-based assays, we're obviously not going to see it with liquid-based assays.
There may be some potential exceptions to that. One might be ESR1 mutations because those mutations are detectable frequently in the blood, particularly in patients who have been exposed to aromatase inhibitor therapy with estrogen receptor (ER)—positive disease, seem to be associated with resistance to aromatase inhibitors. However, they also seem to respond to selective ER downregulators (SERDs) like fulvestrant or some of the other, newer SERDs that are coming on the scene. That could be a potential application for liquid biopsy, specifically circulating tumor DNA in breast cancer.
The other potential would be for circulating tumor cells. There are several studies now showing that the presence of circulating tumor cells in the peripheral blood of patients with early-stage cancer, but who are ostensibly otherwise cancer-free without clinical evidence of recurrence, is associated with a higher risk for recurrence. We may be able to use circulating tumor cells to select patients at high risk for recurrence after treatment—even 5 or more years after treatment— then use that to risk-stratify and test novel treatment strategies to reduce the risk for recurrence in that population.Metastatic breast cancer remains an incurable disease. There have been some substantial improvements in clinical outcomes, mainly for those with ER-positive/HER2-negative disease, with CDK4/6 inhibitors. That dramatically changed the management of patients with that breast cancer subtype, which is the most common subtype. They have not yet been shown impact survival. We're awaiting the results of those studies, but they have clearly had a major impact on the morbidity associated with treatment.
For HER2-positive disease, we now have multiple therapies that have been shown to prolong survival. Triple-negative breast cancer (TNBC) remains a challenge. There are a limited number of agents beyond cytotoxic therapies that we have for TNBC and survival remains very short for those patients.