Experts Debate Utility of Genomic Profiling in Daily Practice

Mark E. Robson, MD

Although the potential for next-generation sequencing of breast cancer tumors to improve treatment strategies is widely recognized, questions swirl about the optimal use of such increasingly available technologies in clinical practice for today’s patients.

During the 31st Annual Miami Breast Cancer Conference, two leading researchers debated key aspects of the potential benefits and limitations of employing knowledge gained through current genomic profiling technologies to manage patient care.

Mark E. Robson, MD, attending physician in Clinical Genetics & Breast Cancer Medical Services at Memorial Sloan Kettering Cancer Center (MSK) in New York City, argued that next-generation sequencing is a powerful tool that thus far has proved invaluable in oncology research but has not been established as a useful addition to daily clinical practice.

Kimberly L. Blackwell, MD, a professor of Medicine and director of the Breast Cancer Program at Duke Cancer Institute in Durham, North Carolina, maintained that clinicians could use the technology to steer patients into clinical trials and to identify actionable mutations. “I see the promise of next-gen sequencing every day in my own clinic,” she said.

The Case Against Routine Use

Robson, who specializes in treating young women with hereditary breast cancer and in researching targeted therapies for patients with BRCA 1/2 mutations, began his presentation with an endorsement of the potential for next-generation sequencing to fuel therapeutic advancements.

“I think that we’re in the midst of an incredibly exciting time when it comes to genetics and the application of genetic technologies to cancer treatment,” said Robson. “We’re basically testing this enormous hypothesis that we can move beyond the use of our conventional histopathology in staging and bring genomics in, and by defining the pattern of genomic aberrations within a tumor, improve treatment outcomes.

“But I would emphasize that right now this is very clearly a hypothesis,” he added. “This is not in any way proven that on a routine basis this is necessarily going to be useful.”

At MSK, mutation profiling is conducted using its IMPACT process in which sequences from an individual tumor are analyzed in the context of 341 preselected genes. Somatic mutations including base substitutions, small indels, copy number alterations, and possibly select rearrangements are identified. Robson said there are three potential clinical applications of information gained through tumor sequencing: (1) a variant is identified that is clearly linked to response from an approved drug; (2) a variant is identified that would make the patient eligible for a clinical trial; and (3) a variant is identified that is potentially predictive of response to an approved drug off-study.

In the first instance, Robson said, clinicians do not need “agnostic profiling” to determine whether a patient is a candidate for treatment with an FDA-approved drug since the target already is known and a companion diagnostic test typically is available.

When it comes to clinical trials, Robson said that clinicians can find a list of studies targeting a given mutation using sequencing results but that there may be barriers to participation for the patient, particularly having to travel hundreds of miles to enroll. The patient’s financial resources, performance status, and stage of disease also might rule out trials. Robson noted that it may be appropriate to conduct upfront tumor profiling in large academic centers with broad portfolios of targeted therapy trials, but that clinicians in daily practice and their patients might find trials that are better matches geographically, financially, and physically by using databases and other sources.

As far as treating a patient with a targeted agent identified through sequencing outside the boundaries of a clinical trial, Robson discouraged this practice. “Most potentially risky is the idea that you have a patient, either early stage or late stage, you have a genomic profile conducted, and then you use that information to ad hoc pick a targeted agent that you think is going to be useful for the individual and do the treatment,” said Robson. “How do you know whether or not the particular alteration that you found is going to predict response to the particular agent you would like to use?”

In order to sort out the complex information that results from next-generation sequencing, academic institutions including MSK are taking a “tumornormal” approach in which mutations in the normal variations are subtracted from the tumor variations to gain more clarity, said Robson. By contrast, he said commercially available tests compare tumor samples to a set of reference genes and might generate information about rare germline variants or somatic mutations that are not relevant to the patient’s cancer. “The variant may not be what’s actually killing the patient,” he said, noting that institutions are moving toward tumor-normal analyses in an attempt to gain more clarity.

Beyond these arguments, Robson noted that it has not yet been established that therapy directed through next-generation sequencing necessarily will produce better outcomes than treatment managed by physicians.

“On a broad basis of this as a generic approach to patients, we need to do the work and do the studies to prove that this is more than a hypothesis— that it is indeed the way we need to move forward in the brave new world,” said Robson.

The Value in Clinical Use

Blackwell, who served as principal investigator on a pivotal study for ado-trastuzumab emtansine (T-DM1; Kadcyla), focused on the potential for next-generation sequencing to improve treatment for women with metastatic breast cancer. The need to find therapies for patients whose disease is not HER2-driven or estrogen receptor—positive is particularly pressing, Blackwell indicated.

Kimberly L. Blackwell, MD

“I’m looking for a revolution in the way we take care of breast cancer patients. In particular for metastatic breast cancer patients, many of our patients do not live any longer today than they lived two decades ago,” said Blackwell.

Blackwell cited three reasons for her contention that sequencing is a valuable tool for oncology practice today: (1) identifying potential clinical trials; (2) moving forward with next-generation sequencing trials; and (3) identifying prognostic mutations. Although Blackwell agreed that patients often have difficulties traveling to clinical trials aimed at a given mutation, she said instances in which a study would particularly benefit an individual make it worthwhile to help figure out a way to get that person enrolled. “There are going to be haves and have nots as we move forward in the next-generation sequencing onslaught,” said Blackwell. “It is pretty tragic to have a patient who knows enough to ask for the sequencing but doesn’t have the resources to get to where they need to go, and we will as a society have to think very carefully about how we do that.”

As an example of the potential benefits, she noted that researchers at Washington University in St. Louis found 25 patients with HER2 somatic mutations whose tumors had tested negative for HER2 amplification among nearly 1500 patients in clinical studies,1 a finding that helped lead to an ongoing phase II trial of neratinib in a similar patient population. She said the trial is open at more than 20 centers, noting that it might be possible to help eligible patients connect with a site.

“The next big thing in metastatic breast cancer is going to come from trials like this, where you have to screen 100 patients to get one patient who has a very high probability of benefiting from the medication,” said Blackwell.

As far as next-generation sequencing trials are concerned, Blackwell pointed to a proposed National Cancer Institute study in which tumor biopsies and sequencing would be conducted at progression to identify resistance mechanisms and match patients with potential therapies.

The MATCH trial, as it is called, would involve screening 1500 to 3000 patients who progressed following standard therapy to enroll 500 to 1000 patients in multiple, single-arm phase II trials.

Seventy-five percent of the tumors to be studied will be common solid malignancies, including breast and non-small cell lung cancers, while 25% will be rarer subtypes of tumors.

Finally, next-generation sequencing is useful for defining prognosis and identifying potentially actionable mutations with immediate benefit to patients, said Blackwell. She said that understanding on a genomic level why certain patients do well on a particular therapy would be helpful in determining the next steps when that patient stops responding.

Much can be gleaned even from limited patient populations, as Blackwell’s own research has shown. Blackwell and colleagues conducted whole-exome sequencing on matched specimens of germline DNA, primary tumor, and metastatic tumor from 34 (out of 38) patients with newly diagnosed metastatic triple-negative breast cancer.² Although no single driver mutation was found, there were from 4 to 8 mutations associated favorably or unfavorably with progression-free, disease-free, and overall survival, Blackwell said.

These included actionable mutations with agents already studied in breast cancer, including p53 and mTOR inhibitors, and other mutations with agents not yet studied in breast cancer (eg, ROS1 inhibitors). “These are the baby steps of figuring out how to use genetic sequencing in the clinic,” Blackwell said.

Blackwell said that next-generation sequencing would help link the revolution in oncology science with clinical applications. “In the successes we’ve truly seen in cancer, we’ve been able to find generator mutations—not just driver mutations but the whole meat and potato of why that tumor gets up in the morning kind of mutations,” she said.

In conclusion, Blackwell urged her colleagues to incorporate next-generation sequencing into their practices. “Don’t be an evolutionist, be a revolutionist when taking care of your breast cancer patients,” she said.

References

1. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer [published online December 7, 2012]. Cancer Discov. 2013;3(2):224-237.
2. Blackwell KL, Hamilton EP, Marcom PK, et al. Exome sequencing reveals clinically actionable mutations in the pathogenesis and metastasis of triple negative breast cancer. Presented at: 38th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S4-03.