Molecular Profiling in Breast Cancer: Still Not Ready for the Clinic

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The “new taxonomy” of breast cancer and molecular subtyping of tumors are “making clinical sense” to oncologists, but molecular tools that describe these cancers are still not ready for routine use, according to Joyce O’Shaughnessy, MD, of Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas.

At the 2013 Breast Cancer Symposium, O’Shaughnessy described the latest research to truly personalize breast cancer treatment by molecular profiling but cautioned that these tests should not be driving treatment outside of clinical trials.

“Clinicians are mainly still using routine pathology and immunohistochemistry, but we can see the future, where there will be a new taxonomy for many cancers based on pathway activation, the tumor microenvironment, and the presence of cytokines, immune-based mediators, and the like,” she said. “There is likely to be a different taxonomy for breast cancer than what we use today, but we are at the infancy of this process.”

Best Use of Molecular Tools: Triaging Patients to Clinical Trials

“We all agree that to stem the spiraling cost of cancer treatment, concerted efforts are needed to develop molecular diagnostics that will better identify patients who will respond to expensive therapies,” O’Shaughnessy said. “My own opinion is that in today’s clinical practice, next-generation sequencing and other molecular tools have most utility in triaging our patients to clinical trials, a number of which are selecting participants based on molecular characteristics.”

She pointed out that targeted therapy based on a single gene marker is unlikely to be of high clinical utility at this time. Inhibition of what appear to be “clear targets” can be ineffective due to de novo or acquired resistance or alternative pathway activation. “These are the pitfalls we face if we try to match molecular abnormalities with targeted agents, off label,” she said. The off-label use of targeted agents, therefore, is not recommended.

Looking to the Future

“We are just beginning to have a few data sets to give insights into how molecular profiling tools can help us in practice,” she said.

One is the Caris Life Sciences database of more than 35,000 tumors (all the common tumors, some rare tumors), for which driver gene mutations, copy number alterations, and protein expression patterns were described. Numerous targets were discovered that had the potential to be treated with targeted therapy not usually considered for the cancer type.¹

“This is a rich data set that has yielded several key findings,” she said. “For our patients who have proven unresponsive to standard therapy, these kinds of tests can help us understand whether the patient might benefit from, for example, a cMET inhibitor trial. The real power of such a test, again, is to understand which patients might benefit from a particular clinical trial.”

Daniel Von Hoff, MD, director of translational research at the Translational Genomics Research Institute in Phoenix, Arizona, and colleagues reported the potential clinical utility of this broad molecular profiling in 66 metastatic patients.² They compared progression-free survival (PFS) using a treatment selected by molecular profiling of the tumor with PFS from the patient’s most recent regimen. Of these patients, 27% had a PFS that was at least 30% longer than their last unselected treatment. A follow-up study in metastatic breast cancer is under way.

Foundation Medicine has also used next-generation sequencing to study actionable mutations (for which there are approved or investigational matched agents) in 169 breast cancer patients. They found that 90% of patients had actionable mutations, averaging 1.9 per patient.³ “This is our first view into what is found if next-generation sequencing is done on paraffin tissues of metastatic breast cancer patients in the community,” O’Shaughnessy noted.

Other work by this group in 44 metastatic breast cancer patients found at least 1 molecular alteration in 98% of patients; about a dozen common mutations were identified, while dozens of rare mutations were observed in small percentages of patients. A phase 1 targeted agent was given to 73% of the patients with mutations, and 44% of these patients achieved a response or stable disease.⁴

Finally, O’Shaughnessy said she is especially interested in the concept of the “exceptional responder” and how these patients might guide treatment. The National Cancer Institute is leading an effort to locate trial participants who respond exceptionally well to the study agent, and then genotype those individuals.

“An ‘N of 1’ could be hypothesis-generating,” she said. The identification of the responding phenotype could lead to the description of the genotype, and this could be used not only to select patients for clinical trials of new agents but also in the clinic, she suggested.

“Over time, with larger numbers of patients, this could identify which mutations are essential to the exceptional responder genotype and could ultimately identify high-value therapies,” she said.

References

1. Gatalica Z, Millis S, Chen S, et al. Integrating molecular profiling into cancer treatment decision making: experience with over 35,000 cases. J Clin Oncol. 2013;31(suppl). Abstract 11001.
   
2. Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;33:4877-4883.
   
3. Ross JS, Cristofanilli M, Downing S, et al. Use of the FoundationOne next-generation sequencing (NGS) assay to detect actionable alterations leading to clinical benefit of targeted therapies for relapsed and refractory breast cancer. J Clin Oncol. 2013;31(suppl). Abstract 1009.
   
4. Miller VA, Ross JS, Wang K, et al. Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: the Foundation Medicine (FMI) experience with 2,200+ clinical samples. J Clin Oncol. 2013;31(suppl). Abstract 11020.

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