New Tools Enhance Molecular Portraits of Breast Cancers.

Using a combination of analytical tools, investigators with The Cancer Genome Atlas (TCGA) Research Network have completed a molecular study of breast tumors from 825 women. The results, recently reported in Nature, confirm the existence of four major subtypes of breast cancer and add new details about the biological changes underlying these diseases.

The researchers used up to six different technologies to characterize subsets of the tumors. In addition to sequencing DNA and RNA, the investigators profiled patterns of DNA methylation and counted the number of copies of genes in tumors. This was also the first TCGA study to report protein expression patterns in tumor samples.

The integration of these results has given researchers a catalog of the genetic and epigenetic abnormalities in each subtype of breast cancer, underscoring the idea that these tumors are, in many respects, distinct diseases.

“This paper and five others [describing breast cancer genomes] published this year in Nature provide a new roadmap for translational and basic research on breast cancer,” said co-lead investigator Dr. Matthew Ellis of the Washington University School of Medicine in St. Louis. Researchers could spend a decade following up on these results, he added. (See the sidebar for links to the study abstracts.)

Previous studies had hinted that one of the subtypes, basal-like breast cancer, was genetically similar to a form of ovarian cancer. The TCGA study confirmed this idea and suggested that treatments currently being tested for some ovarian cancers could be tested against these breast cancers.

“This finding really stood out,” said Dr. Ellis. “And it led to discussions [among the study authors] about the most appropriate types of chemotherapy for patients with breast cancer.” The other subtypes are known as luminal A, luminal B, and HER2-enriched breast cancers.

Making Use of Multiple Technologies

Speaking at a press briefing on cancer research last week, NCI Director Dr. Harold Varmus acknowledged that the four breast cancer subtypes have been known for years. What’s new, he explained, is that, for each subtype, TCGA investigators used multiple technologies to describe the “landscape of genetic abnormalities” in greater detail than in the past.

The Six Nature Studies

“We haven’t had a storehouse of so much valuable information about each of these categories of cancer, with the same tumors analyzed for a wide variety of properties,” he said. “It’s the repository that is so important.”

Because the study included hundreds of tumors, the researchers were able to detect uncommon but recurring mutations. Some of these mutations indicated that the tumors might respond to existing drugs. “Repurposing drugs will be important for treating this disease,” said Dr. Ellis.

Even if a particular mutation occurs in only 2 percent of patients, Dr. Ellis continued, breast cancer is common enough that researchers should be able to enroll enough women in clinical trials to test existing drugs that target these mutations.

About 20 percent of the patients with basal-like tumors might be candidates for drugs known as PARP inhibitors based on analyses of the genes BRCA1 and BRCA2 in their tumors, the researchers said. The group of basal-like tumors includes triple-negative breast cancers, which are difficult to treat and disproportionately affect younger women and African Americans.

The Translation Phase

Only three genes—TP53, PIK3CA, and GATA3—were mutated in more than 10 percent of the patients’ tumors. Drugs that target changes resulting from defects in PIK3CA are in development and could be tested in selected patients with breast cancer. However, designing and implementing large clinical trials can take years, the researchers cautioned.

“People always want to know when this kind of research is going to affect clinical care,” said Dr. Charles Perou of the Lineberger Comprehensive Cancer Center at the University of North Carolina, another study leader. “Now that we’ve made these discoveries, we’re in the translation phase.”

Many of the new discoveries can now be tested in the context of clinical trials. For instance, the study suggested there may be at least two groups of patients with HER2-positive tumors, and these groups may have different responses to treatment.

“We had a hint of this from past gene-expression studies,” said Dr. Perou. But the integrated results of the TCGA analysis, which included proteomics, are “far more convincing and suggestive than results based on any one technology alone.”

Dr. Perou co-authored one of the first studies to use genomics to distinguish subtypes of cancer. The study, published in 2000, used what was then a new tool—DNA microarrays—to profile the expression of 8,000 genes in breast tumors from 42 women.

More than a decade later, the technological advances in genomics have been “astonishing,” noted Dr. Ellis. The missing component right now is information about proteins and the biochemistry of cancer cells, he observed.

“Over the next 10 years, we need to study proteins in the same way that we have just studied DNA and RNA over the last decade,” said Dr. Ellis. Only then, he added, “will we develop a complete picture of the biochemistry of cancer cells.”

Source: NCI



Lung Cancer Genome Surveys Find Many Potential Drug Targets.

Five new studies have identified genetic and epigenetic alterations in hundreds of lung tumors, including many changes that could be targeted by drugs that are already available or in clinical testing.

The reports, all published this month, included genomic information on more than 400 lung tumors. In addition to confirming genetic alterations previously tied to lung cancer, the studies identified other changes that may play a role in the disease. (Links to the study abstracts appear in the sidebar below.)

“These five papers are the first major salvo of genome-wide studies using all of the newest technologies to analyze a large number of lung cancers,” said Dr. John Minna, a clinician and lung cancer researcher at the University of Texas Southwestern Medical Center, who co-authored one of the studies.

Collectively, the studies covered the main forms of the disease—lung adenocarcinomas, squamous cell cancers of the lung, and small cell lung cancers.

Although preliminary, the findings could be used to develop molecular markers for identifying patients who are candidates for certain targeted drugs. At the same time, researchers in the lab can now evaluate the newly discovered changes to identify novel potential therapeutic targets.

“All of these studies say that lung cancers are genomically complex and genomically diverse,” said Dr. Matthew Meyerson of Harvard Medical School and the Dana-Farber Cancer Institute, who co-led several of the studies, including a large-scale analysis of squamous cell lung cancer by The Cancer Genome Atlas (TCGA) Research Network.

Some genes, Dr. Meyerson noted, were inactivated through different mechanisms in different tumors. He cautioned that little is known about alterations in DNA sequences that do not encode genes, which is most of the human genome.

Squamous Cell Tumors

The TCGA investigators sequenced the genomes or exomes (the protein-coding regions of DNA) of tumor samples from 178 patients with squamous cell lung cancer. In more than half of the tumors examined, the researchers found a change to a gene or a signaling pathway that is targeted by a drug that exists or is in development. The findings were reported in Nature on September 9.

“This gives us an enormous opportunity for progress in this disease,” said Dr. Meyerson.

The TCGA model integrates genomic data for squamous cell lung cancers with clinical information, when available, and with other tumor characteristics, such as gene expression, epigenetic changes to cells, and alterations in the number of gene copies.

“The framework for these five studies was built on a convergence of new technologies and the need to better understand the biology of lung cancers as it relates to new therapies for our patients,” said Dr. Paul Paik, who treats patients with lung cancer at Memorial Sloan-Kettering Cancer Center and was part of the clinical team involved in TCGA.

Small studies (for example, here and here) have provided hints that certain signaling pathways are important in squamous cell lung cancers, leading to new trials of targeted drugs. “Now, with the publication of the TCGA study, we know that squamous cell lung cancers have a myriad of potentially targetable changes,” Dr. Paik noted.

An unexpected finding was the presence of mutations in the EGFR gene in about 1 percent of squamous cell tumors. These tumors might respond to available drugs that block signals through the EGFR pathway.

The researchers also found evidence of genetic changes that may help lung cancer cells evade surveillance by the immune system.

The Five Studies

Testing Lung Tumors

Any therapeutic targets to emerge from the new reports would need to be incorporated into molecular tests that can identify candidates for certain drugs. A leader in this work is the Lung Cancer Mutation Consortium, which has been building knowledge of the mutations associated with the disease and testing for these changes.

Many patients with lung adenocarcinomas have benefited from targeted drugs. Crizotinib (Xalkori), for instance, has elicited some dramatic responses in patients whose tumors harbor a particular gene fusion. Some medical centers now routinely test tumors before selecting treatment for patients with lung adenocarcinomas.

“If you look at lung cancer as a whole, the big therapeutic targets were first identified in adenocarcinomas,” Dr. Minna explained. “Now there are new targeted therapies that could make an impact on squamous cell lung cancer.”

At Memorial Sloan-Kettering, all patients with squamous cell lung cancer have their tumors tested for drug targets using various techniques, including DNA sequencing. Among 28 of these patients evaluated recently, more than 60 percent had tumors that contained a potential target.

Dr. Paik noted that his group will use the TCGA results to expand their testing. “In a sense, the future potential of this new work is being realized now,” he said. “That’s pretty exciting.”

Small Cell Lung Cancer

Two new reports describe genetic changes in small cell lung cancers, which tend to be aggressive and about which little has been known. The research teams conducted exome or whole-genome sequencing on a total of 82 samples of such tumors.

“This study gave us a host of new targets to explore,” said Dr. Charles Rudin of the Johns Hopkins Kimmel Cancer Center, who led one study. The next steps will be to validate which targets are driving the growth of tumors and are “druggable,” he added.

The researchers found that a gene called SOX2, which plays a role in normal development, may contribute to some small cell lung cancers, as well as other cancers, and could be targeted.

Small cell lung cancers have been challenging to study because most are not treated surgically, so tumor samples are rare. What’s more, these tumors have high rates of genetic mutations due to tobacco smoke, yet only some mutations are driving the disease, noted Dr. Roman Thomas of the University of Cologne in Germany, who led the other study.

Using statistical “filters,” his group found that genes involved in modifying histone proteins, which help package DNA within a cell, were frequently mutated in the disease.

“These cancers are extraordinarily complex, so as researchers our steps forward are incremental—but, still, they are steps,” Dr. Thomas noted. “No one would have imagined that lung cancer would be the prototypical disease for targeted medicine.”

Comparing Tumors in Smokers and Nonsmokers

Non-small cell lung cancers were the focus of two additional studies, which appeared in Cell. One group sequenced the exomes or genomes of 183 tumor samples, and the other conducted whole-genome sequencing of tumor tissues from 17 smokers and nonsmokers.

“We found a substantially lower number of mutations in the genomes of tumors from nonsmokers compared to the smokers,” said Dr. Ramaswamy Govindan of the Washington University School of Medicine in St. Louis, MO, who led the study. Five study participants who had never smoked had a mutation that could be targeted by an existing drug.

All these studies show how diverse and how complicated the cancer genome is. But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.

—Dr. Ramaswamy Govindan

In all, the study authors found 54 genes with potentially targetable alterations in the 17 patients.

“The days of large clinical trials for lung cancer are over,” Dr. Govindan said, noting that patients need to be selected for specific treatments based on the characteristics of their tumors. “We also need to develop clinical trials that move targeted therapies to earlier stages of lung cancer, where we have a better chance of a cure.”

Future clinical trials, he predicted, would look for relatively large effects of drugs in selected patients. Dr. Minna agreed, saying, “If the effects are not there, we will move on to the next target and the next drug.”

The new results are really a teaser for what’s coming. TCGA plans to sequence a total of 500 adenocarcinomas and 500 squamous cells tumors. These results could help shed light on issues such as epigenetic changes in lung cancer, mechanisms of drug resistance, and how tumors are influenced by the surrounding tumor microenvironment.

“All these studies published back to back show how diverse and how complicated the cancer genome is,” Dr. Govindan said. “But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.”

Dr. Minna added, “After treating thousands of patients with lung cancer and not doing too well, I am very excited about the new results.”

Source: NCI