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Multi-omic molecular profiling guide's efficacious treatment selection in refractory metastatic breast cancer: a
Mariaelena Pierobon1, Nicholas J Robert2, Donald W Northfelt3
1George Mason University, Manassas, VA, USA.
Abstract:
This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi-omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA-Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP-selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow-up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11-22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan-based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan-based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.
Insights
Multi-omic molecular profiling (MoMP) identified actionable targets in 92% of refractory metastatic breast cancer (MBC) patients. Over half achieved clinical benefit, demonstrating MoMP
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Refractory metastatic breast cancer (MBC) presents significant treatment challenges.
- Personalized medicine approaches are crucial for optimizing therapy in advanced cancers.
- Multi-omic molecular profiling (MoMP) offers a comprehensive view of tumor biology.
Purpose of the Study:
- To evaluate the clinical utility of MoMP for guiding treatment selection in refractory MBC.
- To assess the rate of targetable alterations and clinical benefit using the Growth Modulation Index (GMI).
- To investigate the role of specific biomarkers, such as TOPO1, in predicting treatment response.
Main Methods:
- Prospective phase II clinical trial (Side Out 2) involving 32 patients with refractory MBC.
- Multi-omic molecular profiling (MoMP) including exome sequencing, RNA-Seq, IHC, and RPPA.
- Treatment selection based on MoMP findings, with clinical benefit assessed by GMI (≥1.3).
Main Results:
- MoMP identified targetable alterations in 92% (23/25) of patients.
- 56% (14/25) of patients achieved a GMI ≥1.3, indicating clinical benefit.
- High TOPO1 expression guided irinotecan-based therapy in 48% of patients, showing a 66.7% GMI ≥1.3 response rate.
Conclusions:
- MoMP is effective in identifying actionable alterations in refractory MBC.
- MoMP-guided treatment selection leads to clinical benefit in over half of heavily pre-treated patients.
- This approach facilitates biomarker discovery and informs personalized therapy selection for MBC.
