Multi-Omics Approach to Personalized Therapy Shows Feasibility in Metastatic Breast Cancer

Ben L. Kong, PharmD

A multi-omics approach to personalized therapy that incorporates information about actionable oncogenic drivers with critical biological data has demonstrated feasibility in patients metastatic breast cancer vs DNA sequencing alone, according to data from a study presented during the virtual AACR Annual Meeting 2021.

“We demonstrate the feasibility of implementing a deep real-time analytics platform for [patients with metastatic breast cancer] that can provide new insight into therapeutic opportunities,” Ben L. Kong, PharmD, of Oregon Health & Science University, said during a presentation of the data. “The observed clinical responses support the use and investigation of this approach.”

The SMMART program, which stands for Serial Measurements of Molecular and Architectural Responses to Therapy, has multiple clinical and research objectives such as real-time adaptation of therapy to each patient’s needs, durable and tolerable tumor control over the life of the patient, and the ability to identify resistance mechanisms and biomarkers of cancer treatment.

When the patient enters the program, data are generated to design a therapy plan. Patients are then monitored over the course of treatment to identify tumor response. If progression occurs, they are invited back to obtain additional biopsies.

“Internally, the program is collecting a large amount of data. We start off with a tumor biopsy and blood followed by clinical data and also anatomic imaging,” Kong said. “All the information that we collect are then passed along to the data management system, which then is available for both the research tumor board and the clinical tumor board to review and access.”

From January 2017 to January 2020, 53 patients consented for screening and biopsy with 38 patients enrolled. After analytics were generated and disease progression occurred, patients were assigned to either a matched or an unmatched therapy.

The multi-omics clinical tumor board was presented DNA- and RNA-level data, such as whole-exome sequencing and whole-transcriptomic sequencing, and laboratory results such as immunohistochemistry and tumor markers. After that, optimal therapy management was recommended, consisting of either additive care, off-label treatment, or a clinical trial.

Enrolled patients had a median age of 56 years (range, 32-75), were majority White (89%), and had a median of 3 prior lines of therapy (range, 0-13); all patients were female. Most biopsies (n = 63) were collected from the lymph nodes (35%), liver (27%), soft tissue (11%), or bone (10%). Fifteen patients had serial biopsies taken, which consisted of 2 or more samples.

A cutoff of 1.3 for the ratio of second progression-free survival (PFS) to first PFS (PFS2:PFS1) was used in the 12 patients who received match therapy. Of those, 8 patients had a PFS2:PFS1 ratio that met or surpassed the predetermined threshold.

Kong specifically detailed the results in 3 patients treated with matched therapy. The first had tumor heterogeneity identified through serial biopsies but was initially found to be estrogen receptor (ER)–positive with tamoxifen administered at disease recurrence. Subsequent biopsies in the liver following mixed responses revealed some to have ER-negative and triple-negative histologic subtypes. Unfortunately, treating clinicians were not able to determine an effective therapy for this patient.

In another case, a novel combination of a checkpoint plus a PARP inhibitor was used in a patient with serial biopsy monitoring. Of note, apparent mechanisms of resistance in the MAP kinase pathway were revealed and the patient was switched to bridging therapy with chemotherapy for tumor disease management. Discussion by a tumor board led to the patient receiving a PARP inhibitor plus the MEK inhibitor cobimetinib (Cotellic).

Another patient with an exceptional tumor response initially presented to the program on doxorubicin therapy with rising tumor markers and a progressing liver lesion that was identified as ER negative and HER2 negative with an activating ERBB3 activating mutation. Research analytics also came back indicating activation along the HER2 axis. As a result, the patient was started on trastuzumab (Herceptin) with a dramatic decrease in tumor markers.

“The best way to fulfill the essence of the tumor board is to make sure that the best treatment is recommended,” Kong said. “[We want to] make sure that we identify the best treatment that matches with the evidence.”

Reference

1. Kong BL, Johnson BE, Keck JM, et al. SMMART Program: a multi-omics tumor board with a focus on breast cancer. Presented at: American Association of Cancer Research Annual Meeting 2021. April 9-14, 2021. Abstract LB010.