A pilot study utilizing molecular profiling to find potential targets and select individualized treatments for patients with metastatic breast cancer.

Abstract

TPS11123 Background: The objective of this prospective pilot study was to determine if treatment selected by molecular profiling (MP) of metastatic breast cancer (MBC) tumors at time of disease progression provides greater clinical benefit than empiric treatment selection. Methods: Eligible pts had MBC, ≥ 3 prior lines of therapy, and > 6 wks - < 6 months time to progression on last treatment prior to study entry. Fresh core biopsy samples were taken from the metastatic site for MP. Analysis by IHC, FISH, DNA microarray and reverse phase protein microarray (RPMA) a quantitative protein pathway activation mapping technique using laser capture micro dissected tumor cells was done, with results in ≤14 days reviewed by a Treatment Selection Committee. The primary objective was to compare the progression-free survival (PFS) using a MP selected treatment regimen to the preceding PFS. Clinical benefit for the pt is defined by PFS ratio (PFS on MP selected therapy/PFS on prior therapy) is ≥ 1.3, (JCO,28:4877-83:2010). N= 25 was determined (exact single-stage design for phase II studies, type I error rate of 5% [one-sided], power of 90%). MP selected therapy would warrant further investigation if ≥ 35% of the pts demonstrate a PFS ratio of ≥ 1.3. Results: Three U.S. sites enrolled 25 evaluable pts who were treated based on MP results. Pts were heavily pretreated with 4 -11 prior therapies (median 7.24). Ten pts (40%) met or exceeded the PFS ratio of 1.3. The most common targets used in drug treatment selection were TOPO1, TS, ER/PR, TOP2A, HER2. Sixty percent of pts’ samples had activation of drug targets determined by RPMA in 3 major clusters: pan-HER-AKT; EGFR/SRC/ERK/mTOR; IGFR/RAF/MEK/PLK1. Days on MP selected treatments range from 9 - 816+. 3 pts continue on treatment for 199, 254 and 816 days. Conclusions: This study demonstrates the feasibility of a highly multiplexed genomic and proteomic MP study for treatment selection in a timely fashion. Patient-specific target driven treatment selection based on MP of a metastatic lesion provided clinical benefit for 10 of 25 heavily pretreated MBC pts. Thus, this approach merits further investigation in future studies. Funded by The Side-Out Foundation. Clinical trial information: NCT01074814.

Metastatic Salivary Gland Tumors: A Single-Center Study Demonstrating the Feasibility and Potential Clinical Benefit of Molecular-Profiling-Guided Therapy

“…Previous studies have demonstrated the feasibility and potential clinical benefit of the MP-guided approach in a variety of refractory cancers and in metastatic breast cancer where it resulted in a ≥30% longer progression-free survival than for the last (pre-MP) regimen on which the patients progressed in 27% and 52% of cases, respectively [ 17 , 18 ]. Although the progression-free survival ratio endpoint was inappropriate for our study, as most of the patients did not receive pre-MP chemotherapy for metastatic disease, our findings are compatible with these earlier studies and support the need for further investigations of MP-guided therapy.…”

“…It involves the application of immunohistochemistry (IHC), fluorescent/chromogenic in situ hybridization (FISH/CISH), microarray analyses, sequencing, and reverse transcription polymerase chain reaction (RT-PCR). Treatment based on MP findings has proved successful in a pilot study of a variety of refractory cancers and a separate study of metastatic breast cancer [ 17 , 18 ].…”

A practical approach to aid physician interpretation of clinically actionable predictive biomarker results in a multi-platform tumor profiling service

“…A recent study in patients with refractory breast cancer showed that tumor profiling resulted in a revision of the original treatment decision for all patients. Tumor profiling based therapy resulted in a clinical benefit in 52% of heavily pretreated patients ( Jameson et al, 2013 ). A review of all patients treated in a single center in Australia resulted in clinical and survival benefits in over half of the patients and confirmed the role of molecular profiling in a clinical practice setting ( Dean and Wallace, 2013 ).…”

Impact of upfront cellular enrichment by laser capture microdissection on protein and phosphoprotein drug target signaling activation measurements in human lung cancer: Implications for personalized medicine

“…Indeed, this high‐throughput multiplex platform allows for broad investigation into the changes in the signaling architecture of the malignant cells starting from very small amounts of biological material such as a core needle biopsy. Moreover, by constructing each array with built in standard curves and controls, the RPPA platform is currently capable of delivering quantitative information that can be easily used for stratifying patients for individualized treatment .…”