Genomics and Sequencing


The OSUCCC – James is both incorporating precision cancer medicine (PCM) in the clinic and advancing it through research.

The story of the epidermal growth factor receptor (EGFR) as a target of cancer therapy illustrates the development and advantages of PCM. By the late 1990s, clinical trials were underway to evaluate whether the drug gefitinib, designed to block EGFR signaling, was effective for non-small-cell lung cancer.

The drug gefitinib was the first of the EGFR inhibitors (erlotinib soon followed). 

The original gefitinib trials tested all patients with non-small-cell lung cancer, and the results were mildly encouraging. About 10 percent of American patients with NSCLC responded quickly with stabilized disease and other partial responses, while other patients showed little or no response. In Japan, a gefitinib trial showed 27 percent of patients experienced partial responses.

The drug seemed moderately promising. Afterward, two separate research groups sequenced EGFR genes from patients in the two trials to investigate why some patients responded better than others. The two groups reported their results simultaneously in 2004, one group in the New England Journal of Medicine, the other in the journal Science.

The findings were identical: Patients who responded to gefitinib had specific mutations in the EGFR gene. The results suggested that screening patients for EGFR mutations might identify which patients had gefitinib-sensitive tumors.

The hypothesis that EGFR mutations played a role in gefitinib activity was there at the time, but those original trials were done before OSUCCC – James researchers could test patients in advance.

In 2000, there was a lack of understanding of new genetic alterations that are important for cancer and for drug development, and OSUCCC – James researchers lacked the technology to test large numbers of genes in individual patients.

Today, however, OSUCCC – James researchers can sequence hundreds of genes for under $5,000, which enables them to look at the scope of all the genes we currently think are clinically important in cancer. Testing patients for EGFR mutations is now routine in the OSUCCC – James lung-cancer clinic.

Precision Cancer Medicine at the OSUCCC – James

The OSUCCC – James uses genomic testing to help determine therapy for patients with lung cancer, certain gastrointestinal cancers, melanoma, leukemia and lymphoma, often in conjunction with clinical trials.

This enables OSUCCC – James researchers to include patients in the trial who are more likely to benefit from the therapy and to avoid treating patients who are less likely to benefit. It also enriches studies with patients who are more likely to benefit from the therapy. That should enable OSUCCC – James researchers to conduct trials more efficiently and complete them faster with fewer patients and at lower cost. Hopefully, this will lead to earlier drug approval for those diseases.

In addition, genomics and next-generation sequencing have been the most important advance in lung cancer in the last 10 years. Currently, the James Lung Cancer Clinic routinely tests for EGFR, RAS and 10 other genes to help make treatment decisions.

In 2013, the clinic began using a panel consisting of 50 genes and more than 250 mutations. The panel includes both the clinically important lung cancer mutations and mutations of research interest. The OSUCCC – James is a member of the Lung Cancer Mutation Consortium, and it shares mutation data it collects, plus clinical outcome data, with the national project.

Through the consortium, the OSUCCC – James has also opened clinical trials for inhibitors that target MET, HER2, PIK3ca and BRAF, with a ROS1 trial opening soon. The goal is to match the right drug with the right person based on the molecular characteristics of the patient’s tumor.

A pilot study

A clinical trial designed and led by Sameek Roychowdhury, MD, opened at the OSUCCC – James in November 2013 to evaluate a mechanism that uses precision cancer medicine to refer patients to novel clinical trials that have molecular eligibility criteria.

The study (OSU-13053, NCT02090530) integrates next-generation sequencing and other molecular testing for patients, a multi-disciplinary precision tumor board to interpret the test results, and precision cancer trials that are based on molecular eligibility.

All cancer types are eligible, including advanced, refractory and metastatic disease that are appropriate for early phase trials. Key steps in the Ohio State precision cancer medicine trial include:

  • Genetic counseling to help patients understand the trial’s goals;
  • Obtain a tumor biopsy and a buccal swab or blood sample (for germline analysis);
  • Sequencing and data analysis;
  • Sequence data presented to precision tumor board to identify actionable mutations;
  • Disclosure of clinically important results to patient through a genetic counselor, and to his or her physician.

Patients with particular mutations might receive a certain therapy regardless of the type of solid tumor it is.

Research

OSUCCC – James clinical and basic researchers routinely use high-throughput technology for studies that advance precision cancer medicine.

Exceptional responders

As the story of anti-EGFR therapy for NSCLC shows, identifying mutations that drive cancer development is critical for developing effective targeted cancer therapies and for identifying the patients most likely to benefit from those therapies.

But driver mutations have yet to be identified in over 50 percent of lung adenocarcinomas. Study lead David Carbone, MD, seeks clues to new driver mutations through genomic studies of clinical-trial “super responders,” people who show exceptional drug responses.

A recent multi-institutional study co-led by Carbone and reported in the Journal of Clinical Investigation describes a clinical-trial patient with advanced lung cancer who was treated with the targeted drug sorafenib. Within two months, she experienced a near complete response, and she remained progression-free and asymptotic for five years while continuing sorafenib orally.

The patient was one of nine who responded to the treatment during the 306-patient trial. She had by far the best and longest lasting response to the drug.

Using whole-genome sequencing, Carbone and his colleagues identified more than a hundred alterations in the patient’s cancer genome. The top dozen included a plausible target of sorafenib.

The gene was both mutated and highly overexpressed. The researchers found the same mutation in 1 percent of an independent group of lung cancer cases. They also showed that cells with this mutation formed tumors, and that the tumors were inhibited by sorafenib.

The study suggests that we can discover important new gene mutations that drive cancer development and progression by analyzing genes in cancer cells from patients who fare far better or far worse than others in a particular clinical trial.

Drug resistance

A study published in the New England Journal of Medicine and co-led by OSUCCC – James researchers is an example of how Ohio State researchers use next-generation sequencing to understand how cancers become drug resistant. The work was led by John C. Byrd, MD, and Amy Johnson, PhD.

The findings described two mechanisms of resistance for the new drug ibrutinib, which received accelerated approval from the Food and Drug Administration for chronic lymphocytic leukemia (CLL) and for mantle-cell lymphoma. The agent irreversibly binds with Bruton’s tyrosine kinase (BTK), blocking a growth signal in CLL cells and causing their death.

Using whole-exome sequencing on cell samples from CLL patients who relapsed while taking ibrutinib, the researchers identified two mechanisms of resistance. One involved an amino acid substitution in the BTK binding site; the other involved mutations in a protein downstream of BTK that enable growth signals to circumvent BTK. 

Epigenetics

High-throughput sequencing technology can also detect epigenetic changes in genes that contribute to cancer. Epigenetic changes influence gene expression without affecting DNA structure.

Clara D. Bloomfield, MD, and Guido Marcucci, MD, led a study that used next-generation sequencing to detect an epigenetic change called DNA methylation.

Cells use DNA methylation – they add methyl groups to DNA – to reduce or silence gene expression. Abnormal DNA methylation in cancer cells can silence tumor-suppressor genes.

Published in the Journal of Clinical Oncology, the 2014 study looked at patients with cytogenetically normal acute myeloid leukemia (CN-AML). The researchers identified abnormal methylation in prognostically important mutations in 134 patients, aged 60 years and older.

Bloomfield, Marcucci and their colleagues used the data to formulate a seven-gene score that encompassed both epigenetic and genetic prognostic information. Low scores – in which one or none of the seven genes is overexpressed in AML cells – was associated with the best outcomes; high scores – six or seven genes were highly expressed – were associated with the poorest outcomes.

The researchers believe the seven-gene score could identify novel AML subsets that might help guide treatment. However, genome-based cancer medicine currently does not address important aspects of cancer biology, including:

  • Biopsy sampling error due to tumor heterogeneity;
  • Epigenetic changes;
  • microRNA dysregulation;
  • Cancer stem cells;
  • Tumor microenvironment influences;
  • Nongenomic-based treatment options such as immunotherapy.

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