Proteomic Advances Hold Promise for Precision Medicine

The patient’s metastatic cancer has resisted the trastuzumab and chemotherapy you initially prescribed, and she’s relying on you to devise lifesaving fallback treatment.

A realm of possibilities exist for this scenario: the same treatment at a higher dose, a different chemotherapy, a different monoclonal antibody, an angiogenesis inhibitor, an experimental medication, or any combination of the above.

What new tests can maximize the chances that your patient will obtain the right treatment for her particular case?

Lance A. Liotta, MD, PhD, explained the existing options and highlighted some promising research March 7, 2014, during his presentation, “Application of Proteomics to Biomarker Discovery and Individualized Therapy," during the Miami Breast Cancer Conference.

“In the past, doctors had little option but to rely on ‘gut feelings’ that amounted to little more than guesswork,” said Liotta, codirector of George Mason University’s Center for Applied Proteomics and Molecular Medicine and medical director of its Clinical Proteomics Lab, during an interview in advance of his presentation. “Unfortunately, studies conclusively show that it’s nearly impossible to guess right, which is why it is so exciting and important that proteomics has advanced to the point that it can sometimes eliminate the guesswork.”

Indeed, proteomic tests can provide much information that even genetic analysis cannot. They can, for example, measure activity levels within the signaling pathways of individual tumors, and those signaling pathways functionally drive the growth, activity, and reproduction of cancer cells. Proteomics may also provide narrower options for treatment. “Genetic analysis tells you all the

proteins a tumor is capable of making. Proteomics tells you what few proteins it actually does make and which ones are in use driving growth or invasion,” Liotta said.

“The first bit of information is interesting, but the second one is a lot more practical when you’re selecting among drugs that only work when particular proteins are present.”

Liotta’s presentation explained the capabilities of the few proteomic tests that are commercially available for breast cancer patients right now. One test that measures the HER family of proteins, for example, builds a “molecular profile” of each tumor that measures the levels of EGFR (HER-1), HER-2 and HER-3 and then quantifies specific auto-phosphorylation sites that

appear on each tumor and indicates the degree of activation.

The test then looks at downstream pathways such as the MAP Kinase pathway and the Akt/mTOR cell survival pathway. In all, the test measures the concentration and activity levels of receptors and signaling pathways that are targeted by 10 separate drugs: cetuximab (Erbitux), erlotinib (Tarceva), gefitinib (Iressa), panitumumab (Vectibix), trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), temsirolimus (Torisel), sirolimus (Rapamune), and everolimus (Afinitor).

The same test also looks for the activation and amplification of signaling pathways associated with resistance to many of those same therapies. “You take a small biopsy, you mail it away and 2 weeks later you have a mountain of useful information, both pro and con, to help you decide among a large number of medications. It is, in many cases, hugely valuable,” Liotta said.

Unfortunately, only a few such tests are commercially available right now, but Liotta sees other possibilities for doctors and patients who really need to tap the power of proteomics. “In addition to discussing what’s on the market for everyone, I will explain how doctors can find relevant trials and enroll patients when circumstances make that appropriate,” Liotta said. “The trials I talk about are not for patients with good prognoses under wellestablished standards of care. However, in cases where the alternative for choosing treatment is guesswork, trials may be a very good option.”

Liotta says that the Side Out Trial 2 that uses proteomics combined with genomic profiling to individualize therapy specifically for metastastic breast cancer, is a pioneering trial that directly addresses this need. Another good option for many women is the I-SPY 2 trial. That trial, which will assess up to a dozen experimental medications, doesn’t assign those treatments entirely at random. It also uses commercial and experimental diagnostic techniques to characterize each tumor and select an appropriate treatment before surgery.

The care, moreover, improves as the trial progresses. Data from earlier groups of patients guide decisions about which treatments might be more and less useful for patients enrolled later in the trial.

In addition to summarizing I-SPY and other promising trials, Liotta explains how doctors can use websites, such as NCI.gov, to find trials that would make sense for their individual patients.

“Proteomics is a big area of research right now,” Liotta said. “There are a lot of trials at various stages of planning and enrollment, so it makes sense for doctors to learn how to look.”

To make the discussion as practical as possible, Liotta will frame most of it in case studies, like that of the patient who led off the story, the one who did not respond to trastuzumab and chemotherapy. Each case study will be one familiar to community oncologists who treat breast cancer, and each discussion illustrates in proteomics might help doctors and patients, either directly or through improved tests for other cancer biomarkers that range from microRNA to lipids, sugars and metabolites.

Liotta’s presentation will focus mainly on what’s available now, but it will also mention proteomics research that’s expected to produce valuable new diagnostic tools in the near future.

“There are some very exciting blood tests in the works that could find cancers at very early stages,” Liotta said, “and other tests that could be paired with mammograms to greatly increase the specificity of diagnosis and greatly reduce needless biopsies.”

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