Utilizing Multi-Omic Profiling to Guide Treatment of Metastatic Breast Cancers
By Catlin Nalley
CHIGAGO—A prospective study, recently presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, explored the clinical benefits of treatment-based on Multi-omic Profiling (MoP) compared to empiric treatment selection among patients with progressive metastatic breast cancer (Abstract 1077).
Building off the success of the Side-Out 1 trial, researchers launched Side-Out 2, an open-label, multicenter pilot study that utilized the molecular profile of target lesions to guide treatment decisions.
“No other precision medicine trial is doing this,” noted Emanuel Petricoin, PhD, Co-Director of the Center for Applied Proteomics and Molecular Medicine (CAPMM) at George Mason University. “This [study] is the first and only one to use this kind of multi-omic information for treatment selection support. At the end of the day, the physicians are making the decisions; this is a decision support tool.”
Between 2014 and 2016, patients with previously treated metastatic breast cancer (n=32) were enrolled at four U.S. sites.
Eligible patients included adults with an ECOG performance status of 0-1, no symptomatic CNS metastasis, adequate organ and bone marrow function, and a documented diagnoses of metastatic breast cancer as well as measurable disease accessible to biopsy, according to study authors.
Biopsies were collected from the metastatic lesions of enrolled patients and each sample underwent genomic and proteomic profiling, including exome sequencing, RNA-Seq, IHC, and quantitative phosphoprotein-based protein pathway activation mapping by Reverse Phase Protein Array (RPPA). Researchers utilized whole tissue lysates for each method except RPPA, which used samples obtained from microdissected tumor epithelia.
“We looked at proteins that we know are targets of FDA-approved drugs,” Mariaelena Pierobon, MD, MPH, Research Assistant Professor at CAPMM, told Oncology Times. “We were looking at these drug targets and their downstream substrates and tried to identify which molecular mechanisms are activated in individual tumors and most likely driving the tumors, so that we can then use FDA-approved compounds to modulate the activity of those drug targets.”
To determine the benefit of MoP compared to empiric treatment, the research team evaluated the patient’s progression-free survival (PFS) on MoP compared to their prior treatment. For the study, clinical benefit was defined as “Growth Modulation Index (GMI) ≥ 1.3 assuming that MoP selected therapy would warrant further investigation if ≥ 35 percent of the patients demonstrate a PFS ratio of ≥ 1.3.”
Among the enrolled patients, 29 received MoP-based treatment and 25 met the follow-up criteria of the trial.
Researchers reported that, of these 25 patients, 14 (56%) met or exceeded a GMI of 1.3. Irinotecan based on TOPO1 expression (n=12; single agent n= 6) and capecitabine based on TS expression (n=9; single agent n=3) were the most selected treatments. Among seven patients who received endocrine therapy, three were treated with exemestane plus everolimus. Additionally, according to investigators, based on HER2 amplification/pathway activation, HER2-targeted agents were given to four patients.
“This approach provided clinical benefit for 56 percent previously treated metastatic breast cancer patients, which met the primary objective of the study,” study authors concluded. “Thus, this approach merits further investigation. This study also suggests that irinotecan may be an under-developed drug for metastatic breast cancer patients.”
This research supports the value of MoP as a decision tool in this patient population. “We continue to see evidence that [MoP] is actually providing a clinical impact,” noted Petricoin. “We are seeing a statistically significant increase in PFS, it met the primary endpoint of the trial, and in some ways [the study] replicated the pilot analysis results that we got from Side-Out 1.”
“The strength of the multi-omic approach was the ability to select a drug, as well as eliminate a drug,” added Pierobon. “It has a double function and also helps clean out a bit of the complexity because you can start identifying what is driving an individual tumor.”
Due to the construction of the trial, physicians can choose among FDA-approved therapies, either off- or on-label, according to Petricoin. “If MoP suggests that a patient may respond to an FDA-approved off-label drug, they have the molecular rationale to use it,” he concluded.
“There is the ability to match patients from this mult-omic analysis to existing therapies that could make a difference to breast cancer patients with metastatic disease.”