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Advances in Breast Cancer Biomarkers

Better analytical precision is needed when assessing breast cancer tumors

By Karen Appold

Posted on: February 4, 2013

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Breast cancer biomarkers are molecules expressed in breast cancer tumors that provide important information about the biology of a tumor. Clinicians can use a biomarker's biological characteristics to diagnose a patient, give a prognosis and make recommendations for drug therapies.

Breast cancers can be sub-classified into luminal A and luminal B, basal-like and HER2-enriched subtypes, each with distinct biology, prognosis and response to therapy, explained Torsten O. Nielsen, MD, PhD, FRCPC, professor of Pathology and Laboratory Medicine, associate director, MD/PhD program, University of British Columbia, Vancouver, Canada. "Traditionally, clinicians have used conventional microscopy to look at a tumor. However, because breast cancer tumors look similar to each other, this approach limits our ability to see the distinct biological differences necessary for determining an appropriate diagnosis, establishing a prognosis or suggesting an appropriate treatment."

In addition, "Breast cancer biomarkers, such as those found in the PAM50 gene signature, provide a prognostic score or risk of recurrence [ROR] score beyond the standard pathological variables in all patients. As a result, patients can be given more actionable information about their ROR," said Bruce Seeley, senior vice president and general manager of diagnostics, NanoString Technologies Inc., Seattle.

FISH for Solid Tumors

The clinical utility of fluorescence in situ hybridization assays in lung cancer, gliomas and breast cancer are identified.

Improvements Needed
Despite advances, better analytical precision is needed when assessing breast cancer tumors. "There is a fair amount of discordance among different labs measuring biomarkers on the same sample," said Peter Ravdin, MD, PhD, director of the Breast Health Center, Cancer Therapy & Research Center at The UT Health Science Center San Antonio, San Antonio, Texas. "Standardization is necessary." A big achievement would be to develop a test that could predict which patients will and will not respond to specific chemotherapy agents. "Immunohistochemistry and fluorescent in-situ hybridization (FISH) are the closest we've come to this thus far."

Molecular diagnostic tests, like NanoString's assay based on the PAM50 gene signature, can help physicians to make a more accurate assessment of a patient's prognosis with genomic information. "However, a newer genomic test could be even better because it would have fewer intermediate risks to patients and is available on a decentralized basis," Seeley said.

Distributing molecular diagnostics to local labs will result in faster turnaround times for patients and enable succinct, comprehensive reports from pathologists resulting in enhanced patient care. The decentralized model can help address patient needs beyond the United States by enabling local laboratories to provide testing.

Overcoming Challenges
Next generation sequencing and other genomic technologies, such as arrays, require fresh or frozen tissue to run the test. "Specimens have to be handled very carefully during surgery to obtain the right tissue specimen," Nielsen said. "This can be difficult and expensive."

NanoString's PAM50 assay does not require specimen freezing, and allows pathologists to run tests in their own hospital lab instead of sending samples to a central lab for testing. "This advance affords clinicians the opportunity to accurately and consistently generate measurements that are hard to achieve in the current hospital setting," Nielsen maintained.

PAM50 adds a significant amount of information to standard clinical and pathological information. "By providing a subtype classification based on the fundamental biology of an individual's breast tumor, as well as a prognostic score that predicts the probability of cancer recurrence over 10 years in post-menopausal women with HR+ early stage breast cancer who have been treated with endocrine therapy alone, doctors can make more informed decisions about treatment," Seeley added.

Results from the Austrian Breast and Colorectal Cancer Study Group, which evaluated samples from more than 1,400 patients, showed that 97% of breast cancer samples that passed the pre-specified tissue and RNA metrics yielded intrinsic subtype and ROR results.

"For conventional chemotherapy treatment, a number of drugs go into the cocktail and it's not clear that this one size fits all approach should be applied," Nielsen said. "Although more research needs to be done, we believe that the PAM50 test can help identify the specific chemotherapy regimen that is the best match for major subtypes."

Looking Ahead
Within the next 10 years, Ravdin believes that multi-gene panels will be the next big area of advancement. Multi-gene panels are comprised of multiple biomarkers, and work the same way as biomarkers. "This will allow us to predict which agents will be particularly effective, which will revolutionize the treatment of breast cancer," he said.

Nielsen believes that developing molecular tests based on gene signatures will not only be limited to breast cancer, but will be used to diagnose all types of cancers. "To change standard clinical practice, a very high level of evidence is demanded by the Food & Drug Administration and medical and the scientific communities. This requires a lot of carefully planned and well-executed research," he said.

Karen Appold is a medical writer based in Royersford, Pa.

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