A Broader Approach to Cancer Genomic Testing Yields Results

As the era of personalized medicine dawns, most major hospitals and cancer treatment practices now routinely perform some amount of genetic testing on individual patients’ tumor samples. These tests typically detect a single genetic mutation associated with the tumor type, such as HER2 in breast cancer.

There is a strong rationale to look more broadly, beyond disease-specific genes, in an attempt to identify non-standard therapeutic strategies and targets and to maximize their potential impact. Expanded cancer genomic testing using next-generation sequencing is a logical next step, but important questions must be addressed:

• Is wide-scale genomic analysis of patients’ tumor tissue feasible in a clinical setting?
• Can genomic testing produce actionable information? Can it detect genetic aberrations that may influence treatment? If so, are there available therapies whose impact on the targeted mutation(s) and on patient outcomes can be assessed?

Answers to these questions are beginning to emerge from ongoing research at Cleveland Clinic’s Taussig Cancer Institute. Preliminary results show that expanded cancer genomic testing can be conducted expeditiously, and it frequently identifies potential therapeutic targets. Recently launched clinical trials are evaluating experimental compounds specifically aimed at those targets.

“The consensus of the first year of our study of expanded genomic testing is that we find actionable targets, but we need to have new drugs available more widely,” says Davendra Sohal, MD, MPH, a staff physician in the Department of Hematology and Medical Oncology and the study’s principal investigator. “We are now building that capability to get these drugs to our patients.”

The tumor genomic analysis study has been underway since August 2013. Cleveland Clinic oncologists anticipate enrolling a total of 250 patients with one of 15 solid tumor types that have a historically poor prognosis or limited treatment options.

Tissue samples are sent for next-generation sequencing by Foundation Medicine, a molecular information company specializing in comprehensive genomic analysis of tumors. Each sample is analyzed using the FoundationOne™ genomics assessment test for the presence of one or more of 315 cancer-related genes.

This profile detects several types of DNA alterations— base substitutions, small insertions/deletions, copy number alterations and gene rearrangements. The test includes those genes that show a high frequency of common alterations but also those on the tail of the curve, such as mutations occurring at low frequency but across many different tumor types.

New Clinical Drug Trials Improve Patient Access

Thus far, many of the Cleveland Clinic patient tumor samples have been shown to harbor a defined genetic mutation, Dr. Sohal says. The identification of possible therapeutic targets highlighted the need to increase patients’ access to local treatment options. “We are building those options now,” he says.

Since March 2014, four new Phase II clinical trials testing compounds that may impact the genetic alterations revealed by tumor profiling have opened at Taussig Cancer Institute. Two more are in the planning stages. “With such trials, we hope that many patients will have the option of participating in a targeted drug trial here,” says Dr. Sohal, the studies’ principal investigator.

The clinical trials’ sponsor is Novartis, the pharmaceutical company developing the new compounds. The trials are open at multiple locations nationally in addition to Cleveland Clinic.

With some exceptions, patients with an incurable solid organ or hematological malignancy who have undergone at least one prior treatment are eligible for the trials. The tumor must exhibit a defined genetic mutation susceptible to the targeted drug under study.

The four compounds currently in testing at Cleveland Clinic are:

• BKM120, a PI3-kinase inhibitor. Between 10 and 15 patients will be enrolled in the investigation, excluding those with endometrial, non-small cell lung, breast, prostate and glioblastoma cancers.
• Dovitinib (TK1258), a receptor tyrosine kinase inhibitor. Ten to 15 patients will be enrolled, excluding those with metastatic breast, squamous non-small cell lung, renal cell, endometrial and urothelial cancers or a primary diagnosis of FLT3 acute myeloid leukemia or multiple myeloma.
• MEK162, an MEK inhibitor for RAS/RAF/MEK activated tumors. Ten to 15 patients will be enrolled, excluding those with melanoma, ovarian, colorectal, lung and pancreatobiliary cancers or a primary diagnosis of chronic myelomonocytic leukemia.
• LDE225 (sonidegib), a smoothened Hedgehog pathway inhibitor. Approximately five patients will be enrolled, excluding those with pancreatic adenocarcinoma, medulloblastoma, basal cell carcinoma, chronic myelogenous leukemia, acute myeloid leukemia or acute lymphocytic leukemia.

“We hope that by offering these clinical drug trials in-house we can make a difference for those patients whose tumor testing reveals something for which there is a drug,” says Dr. Sohal. “We have put patients on these trials, and we are already seeing early results.”

Feasibility and Utility — One-Year Follow-up

One of the original goals of the tumor genomic profiling study is to evaluate the feasibility of performing genomic analyses in a real-world setting. After a year of evaluation, Dr. Sohal and his colleagues have developed a streamlined method of tumor testing that allows patient consent, tumor specimen retrieval, processing and shipment, and communication of results to occur smoothly.

Every test result includes molecular details about a patient’s tumor and supporting data suggesting a particular targeted therapy. That information is reviewed by a Genomics Tumor Board comprising several oncologists and translational scientists. The board makes recommendations for treatment, including the new options for targeted drug trials. These findings are relayed to the primary oncologist, who makes final personalized recommendations to the patient.

Photo credit: © Russell Lee