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Best of ASCO 2013: Promises and Challenges of Applying Molecular Profiling to Clinical Practice

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Key Points

  • Histologic classification is now being supplemented by molecular etiology in classifying types of cancer.
  • An increasing number of specific genomic alterations in cancer can now be therapeutically targeted.
  • Logistic and biologic challenges remain in implementing precision and personalized oncology, but collaborative efforts could overcome many of these obstacles.

A “new kind of pathology,” in which anatomy and histology are supplemented by molecular etiology, has been emerging over the past decade and promises better response rates among cancer patients as genomic alterations in cancer continue to be identified and treated with targeted therapies. “The list of genomic alterations in cancer that can be specifically therapeutically targeted is growing rapidly,” reported Shridar Ganesan, MD, PhD, Associate Director of Translational Science at Rutgers Cancer Institute of New Jersey, in a presentation on molecular profiling at the Best of ASCO Chicago meeting on August 9. The presentation incorporated data from education sessions presented at the 2013 ASCO Annual Meeting.

Using non–small-cell lung cancer (NSCLC) as an example, Dr. Ganesan noted that while there are a few histologic subtypes in this cancer, molecular analysis reveals “a large, surprising heterogeneity of different molecular driver events that are seen in histologically identical cancers.” These molecular driver events appear to be crucial to the development and continued growth and proliferation of these cancers, making them critical targets for small-molecule therapies, he added.

The genomic alterations that can be targeted in cancer cells include not only classical activating oncogenes such as ABL, ALT, RET, and JAK, but also tumor suppressors like BRCA1, BRCA2, and PALB2. “Loss of function in those genes leads to an underlying repair defect that can be targeted by certain classes of standard chemotherapy like the platinum salts as well as new small molecules like the PARP inhibitors,” Dr. Ganesan stated.

Impact of IMPACT Study

In the IMPACT study, patients eligible for phase I trials at The University of Texas MD Anderson Cancer Center in Houston had tumor specimens analyzed for the presence of genomic alterations and were matched to appropriately targeted phase I trials if available, or to other phase I trials. Response rates were shown to increase when patients received appropriate molecular therapy.

Out of 2,282 patients with adequate tissue available to be analyzed, 52.2% had at least one molecular aberration. About 20% of patients who were matched to appropriate molecular therapies had stable disease ≥ 6 months, including 2% with complete response and 17% with partial response by RECIST criteria. Patients who had no molecular match and were assigned to other trials had 0% complete response and 14% partial response. Patients with matched therapy also had improved failure-free and overall survival.

“This kind of high response rate in early-phase trials for which therapies are targeted to underlying molecular aberrations is now commonplace,”  Dr. Ganesan said. He added that some response rates were “strikingly high,” including those using imatinib (Gleevec) for patients with chronic myeloid leukemia and the BCR-ABL fusion biomarker (77%) and crizotinib (Xalkori) for patients with NSCLC and the EML4-ALK fusion biomarker (57%).

Challenges Amid Advances

In addition to the increasing number of molecular therapies, the technology for gene sequencing is rapidly improving, which has “led to the overall schema of personalized medicine we are hoping for,” Dr. Ganesan said. In this schema, “when a person has a cancer diagnosis, not only do you get your standard histologic diagnosis, but the tumor is also sent for multiplexed genomic sequencing, which would ultimately lead to a genomic profile that would allow us to select targeted therapy,” he explained. However, he cautioned, there are still many obstacles to implementing this type of personalized treatment.

“There are no established guidelines for what makes an adequate tissue sample for molecular or genomic analysis and what exact platform and type of analysis should be done,” Dr. Ganesan said. “If we are really going to use this to dictate patient care, we need to carefully evaluate the positive and negative predictive values of each test,” he added. “We will have to develop a standardized method to evaluate and validate these assays. We need national guidelines.”

Another problem concerns determining which gene alterations “are truly actionable,” he noted, which should be based on the strength of the evidence that a genomic alteration is driving the growth of the cancer, and the size of the effect to be achieved by intervening.

“Another big problem, of course, is drug access,” Dr. Ganesan added. One of the proposed solutions is to create a “national formulary” of targeted agents against common aberrations along with a registry of administered treatment and patient outcomes.

There are also biologic challenges to applying molecular profiling to clinical practice, including variations in how mutations signal in different contexts, intratumor heterogeneity, and rapid emergence of resistance, compensating mutations, and pathway adaptation, Dr. Ganesan said. Recommendations for preventing resistance include targeting drivers of genomic instability and clonal diversity, combining targeted therapy with immunotherapy and/or chemotherapy, and conducting frequent tumor biopsies to monitor emergence of new aberrations.

Encourage Tissue Donation

In a question-and-answer session following Dr. Ganesan’s presentation, moderator Douglas Yee, MD, of the University of Minnesota, Masonic Cancer Center in Minneapolis, said that patients should be encouraged to donate tissues to be analyzed for genomic aberrations. “I think at least in my practice most patients really would be willing to contribute,” he said.

In an interview with The ASCO Post, Dr. Yee was asked if patients might be discouraged from donating tissue by the decision recently announced by the National Institutes of Health (NIH) to restrict NIH-financed research on the genome of HeLa cells because of the family’s concern about privacy should the full genomic sequence of HeLa cells be published. “The HeLa cells issue was a completely different era and a very egregious case of not informing the patient about what was being done to her, and I think there is no excuse for that,” Dr. Yee said. In the current situation, patients would be fully informed and understand that the specimens would be used for research about clinical outcomes.

Patients with cancer often ask how they could contribute to cancer control efforts, Dr. Yee noted. “When we talk about how to help, we always talk about advocacy and money and donations, but I think there is another component where patients can help by making their tissues available for study,” Dr. Yee said.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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