Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Genomics Alters the Way Cancer is Now Viewed

Most breast and other cancer types continue to be classified and treated based on histopathologic criteria, or the tumor, node, and metastasis staging system.

But genomic technologies, including RT-PCR, microarrays, NGS, and whole-exome sequencing have created a significant revolution in cancer diagnostics, enabling, for example, analysis of gene expression signatures and mutation status to enable more accurate classification with respect to diagnosis and prognosis. And the emerging genomic picture of cancer has resulted in a re-thinking of therapeutic paradigms and standards.

Last August, the Cancer Genome Atlas Research Network (TCGA) reported the results of a massive integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. The TCGA , composed of 14 institutes nationwide, was intended to prospectively enroll at least 1,000 patients to test their tumors for 10 well-characterized genetic changes and match those patients to optimal therapy based on those changes.

The analysis, published in Cell, revealed that some tumors were more likely to be genetically and molecularly similar based on the type of cell from which they arose rather than its tissue site of origin. Since cancer treatment has historically been based on its tissue site of origin, these findings have forced a major paradigm shift.

Previous TCGA studies had shown that single-tissue tumors can be split into several subtypes based on their molecular profile. Interested in identifying patterns of molecular changes that may be common across tumor subtypes regardless of organ of origin, the TCGA researchers focused on identifying patterns of molecular changes common across tumor subtypes regardless of organ of origin. Comparing 12 tumor types, they discovered that some tumors were molecularly heterogeneous (the converged-diverged subtypes) and others were molecularly homogeneous (same-tissue origin subtypes).

The study found that while five tumor subtypes were found to be nearly identical to their tissue-of-origin counterparts, several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers, for example, coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes.

Chuck Perou, M.D., Ph.D., professor of genetics and pathology at the University of North Carolina’s Lineberger Comprehensive Cancer Center, an institution participating in the study, said, “We found that one in 10 cancers analyzed in this study would be classified differently using this new approach. That means that 10 percent of the patients might be better off getting a different therapy. That’s huge.”

What the ultimate clinical impact of this deluge of new characterization remains to be seen, but data continue to reveal a remarkable heterogeneity among cancers, upending previously held classification systems and changing approaches to treatment.

Inter- and Intratumor Heterogeneity

During his presentation at the 2014 ASCO meeting, Jorge Reis-Filho, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, noted that data obtained from sequencing tumors from patients with breast cancer has “revealed a high level of intertumor and intratumor heterogeneity, with very highly recurrent mutations”. He further noted that “It has also become apparent that not every tumor has identifiable driver mutations, and not all drivers of metastatic disease have been identified. “It is only by harnessing from intra-and-intertumor heterogeneity that we have been able to realize the application of precision medicine.”

Primary triple-negative breast cancer (TNBCs), a tumor type defined by lack of estrogen receptor, progesterone receptor, and ERBB2 gene amplification, comprises about 16% of all breast cancers, and exemplifies a moving genetic target.

TNBC remains one of the most difficult cancers to treat, exhibiting overlapping characteristics with both basal-like and BC susceptibility gene 1 and 2 mutant BCs (BRCA 1 and 2). In 2011, Sohrab P. Shah, Ph.D., and colleagues at the British Columbia Cancer Agency showed in 104 TNBC cases analyzed at time of diagnosis, that these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations.

High-throughput RNA sequencing (RNA-Seq), the authors said, revealed that approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, they demonstrated that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA, and PTEN somatic mutations seem to be clonally dominant compared to other genes. In some tumors their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape, and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumor progression.

According to oncologists, ongoing clinical trials of targeted agents in unselected TNBC populations have yet to produce substantial improvements in outcomes, and advancements will depend on their development in target-selected populations.

Becoming a Reality

Dr. Reis-Filho told GEN that the application of precision medicine is beginning to become a reality, in particular for certain forms of cancer, such as non-small cell lung cancer and melanoma. “When it comes to lung cancer,” he noted, “Current treatments differ completely from what they were a few years ago. “Depending on the repertoire of somatic mutations of a particular tumor, a large armamentarium of treatments to target specific mutations is available.”

For example, in prospective clinical trials, the response rates to EGFR-targeted therapies like gefitinib and erlotinib in patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbored EGFR mutations show a clear improvement over traditional chemotherapeutics.

Melanoma treatment with BRAF inhibitors, Dr. Reis-Filho said, provides another example of molecular targeting, but also illustrates the remarkable genomic plasticity of cancers. Studies to date have shown that both BRAF (B-Raf a serine/threonine-specific protein kinase) and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can impact the natural history of melanoma, but do not provide a cure.

“We can use BRAF inhibitors, but the tumors will become resistant. This is one of the concepts that has emerged,” said Dr. Reis-Filho. “Actionable targets have been successfully identified but with single drugs aimed at that specific target seem to result in significant increases in progression free survival, but minor increases in the lifespan of the patient.”

As we accumulate more information on the constellation of mutations within tumors and the interactions between those mutations, researchers are in a better position to understand how to target a tumor more effectively, according to the Memorial Sloan scientist.

“It is very likely that combined treatment will be required, but that approach produces the challenge of toxicity,” he continued, adding that tumors evolve over time and the greater the heterogeneity the bigger the challenge of treatment. “Only by harnessing the variation between tumors and the genetic heterogeneity within tumors we will be able to deliver therapies based on biology rather than empiricism,” he says.

Just how finely this heterogeneity will have to be parsed to attain effective novel approaches to treating individual tumors remains unclear. But investigators agree that the era of treating patients’ cancer based on its organ of origin has ended. Commenting on the May 2014 creation of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) at Memorial Sloan Kettering, described as a unique and intensive endeavor to transform cancer care through genomic analysis of patient-derived tumors, Michael Berger, Ph.D., associated director of the CMO, said, “For some patients, this could be a game changer. We can find mutations in their tumor that suggest they are going to respond to a drug that the oncologist never would have thought to try.”

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