Tumor Genome Profiling Not Ready for Routine Clinical Use

The use of tumor genome profiling to identify actionable or targetable mutations in women with breast cancer is not ready for routine use in clinical practice, according to Hope S. Rugo, MD, director of the breast oncology clinical trials program at the University of California, San Francisco Medical Center.

“We certainly know that there is some benefit from looking at gene expression in predicting the benefit of chemotherapy, but we have seen in a variety of trials that this doesn’t help predict the benefit from specific chemotherapies,” Rugo said during her presentation, “Tumor Genome Profiling: When Should This Be Used for Clinical Decision Making?” at the 32nd Annual Miami Breast Cancer Conference, held February 26–28 in Miami Beach, Florida. “For example, we don’t even know if we should add a taxane to anthracyclines or when we can omit an anthracycline based on these tests.”

The field is currently trying to determine if specific genomic alterations can be looked at to find a specific therapy that is more likely to benefit a patient’s tumor with that alteration. It is anticipated that an increasing number of healthcare dollars will be spent on next-generation sequencing, such as whole-genome and whole-exome sequencing, for a variety of healthcare conditions, as the technology becomes faster and more affordable.

Breast cancer has a number of different candidate actionable genomic alterations; PI3 kinase (PI3K) mutations are by far the most frequent, with all the rest being significantly less common.

“For example, fibroblast growth factor receptor [FGFR] mutations and mutations that flank the FGFR on that chromosome are estimated to occur in about 25% of patients, but whether or not these really correlate with response to that kind of targeted therapy remains to be seen,” Rugo said.

AKT1 mutations comprise about 4% of breast cancers. Therefore, the minimum number of patients needed for a randomized controlled trial is about 200 patients with that mutation. To enroll 200 patients with the mutation, about 5,000 patients would have to be screened. The cost of screening those patients is high and requires a long time and a lot of centers.

“Many of the trials that are trying to enroll patients with tumors with specific mutations are asking centers to enroll who they are already screening, so the question is, ‘Why are they doing the screening?’” Hugo said. “They are doing the screening from a clinical sense to find out whether they can put patients in clinical trials screening for those mutations; that saves money for the trials but it is unclear whether or not that will be a rational approach for the future.”

To date, there is little evidence that currently available targeted therapies can be tailored to patients with breast cancer with specific mutations. In the BOLERO-2 trial, 724 postmenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer who had progressed on an aromatase inhibitor were randomly assigned 2:1 to exemestane plus the mTOR inhibitor everolimus or exemestane alone. Results of the trial showed a significantly longer progression-free survival and a higher response rate for women assigned the combination treatment.

“mTOR inhibitors clearly target PI3 kinase pathway,” Hugo said. “We looked at activating mutations and there was no correlation with response. Response was similar whether patients had a single mutation in pathways that would be affected by this drug vs those [patients] who had wild-type tumors.”

In HER2-positive disease, the CLEOPATRA study randomly assigned women with metastatic breast cancer to first-line placebo/trastuzumab/docetaxel or pertuzumab/trastuzumab/docetaxel, and results showed that pertuzumab/trastuzumab/docetaxel significantly improved overall survival.

“Unfortunately, in the CLEOPATRA trial where biomarkers were looked at, particularly the PI3K status, we know what we have known for many studies like this: We have prognostic ability but not predictive ability,” Rugo said. “Patients who have these mutations have a worse outcome.”

The field is also seeing an increase in “N of 1” case reports being published in the literature; however, Rugo said that these studies, although interesting, do not tell clinicians what to do with the patients that they are seeing in their clinics.

Overall, Rugo concluded that the role of next-generation sequencing is still unclear and it remains, primarily, a research tool. More data and clinical trials will be needed before genome profiling can be effectively incorporated into clinical practice.