The Future of Cancer Care: Therapy Based on Genomics Improves Survival

DNA Strands

Treatment for lung cancer has traditionally been based on the tumor’s histology (what it looks like under the microscope), but a new approach of basing treatment on genomic features has now been shown to result in better survival.

Results from the Lung Cancer Mutation Consortium (LCMC) show that patients who received genotype-directed therapy lived more than a year longer than those who did not.

The evidence that using targeted agents improves survival in lung cancer has been very difficult to show in clinical trials, but the current study shows that such an approach is not only feasible but successful. In fact, the study heralds a new era in the management of patients with a variety of cancers, Dr. Boris Pasche (Wake Forest University, USA) explains.

The Study: The LCMC, a collaborative, 14-center study led by Mark G. Kris, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, tested tumors from 1007 patients with metastatic (spread to distant sites; incurable) lung adenocarcinomas for the presence 10 oncogenic driver mutations and then used the results to select agents that would target the drivers. The study was conducted from 2009 through 2012, and the patients’ tumors were tested for at least 1 gene, with full genotyping (testing for 10 genes) performed in 733 patients. For the other patients, the primary reason for the inability to test for all 10 genes was insufficient tissue.

The Small Print: An cancer driver was found in 466 (64%) of the patients who underwent full genotyping. So-called KRAS mutations were the most frequent, found in 182 (25%), followed by sensitizing EGFR in 122 (17%) and ALK rearrangements in 57 (8%). Less common drivers were other EGFR in 29 (4%), 2 or more genes in 24 (3%); ERBB2 (formerly HER2) in 19 (3%); BRAF in 16 (2%), PIK3CA in 6 (<1%), MET amplification in 5 (<1%), NRAS in 5 (<1%), and MEK1 in 1 (<1%). These results were then used to guide the choice of targeted therapy.

The Evidence: Overall, among 938 patients with adequate data, the median survival was 2.7 years. For patients with an oncogenic driver treated with targeted therapy, the median survival was 3.5 years, for patients with an oncogenic driver who were not treated with targeted therapy, the median survival was 2.4 years, and for patients with no driver identified, the median survival was 2.1 years (P < .001).

Among the different drivers that were identified, the longest survival was seen in patients with ALK-positive tumors (4.3 years).

“We are at the point now where we may be able to offer patients other treatments by studying the genomic features of their cancer. Until recently, we could not afford to do it because it cost about a million dollars for one genome. Now it’s as low as $900 to do the genome of a tumor, and it’s likely that will become even cheaper. And with better software, we would also be able to assess the unique features of that tumor vs other tumors and vs the normal DNA of that patient, and this is really the major change,” he said.

I’m Dr. Michael Hunter, and welcome to the future.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: JAMA. 2014;311:1988-206; Medscape 20 May 2014

Genes Driving Brain Cancer Revealed

This image shows the coding region in a segmen...
This image shows the coding region in a segment of eukaryotic DNA. (Photo credit: Wikipedia)

Researchers at Columbia University (New York City, USA) have identified 18 genes responsible for driving glioblastoma multiforme (GBM), one of the most common (and deadly) forms of brain cancer.

Background: Cancers rely on driver genes to remain cancer. These driver genes are potential targets for therapy. If we can shut the pathway down through this means, the cancer may collapse.

The Research: The investigators from Columbia University (New York City, USA) believe that they have identified the vast majority of drivers for the delay form of brain tumors, glioblastoma multiforme (GBM). The team identified 15 driver genes that had already been discovered in other studies, and 18 new driver genes that had never been implicated in glioblastoma.

My take: This creates a list of the most important targets for GBM drug development. And then? Personalized management of brain cancer. About 15% of glioblastomas are driven by genes that can be targeted with drugs available in the USA today. We need clinical trials to enroll these patients. Of course, given tumors are powered by varying driver genes, a complicated analysis is required before personalized treatment can be offered. Imagine if we could isolate the most aggressive cells from a tumor, identify the driver gene responsible for its growth, and test drugs on the isolate cells to find the optimal therapy. Some of these genes are in cancer stem cells, the tumor’s most aggressive cells.

For the 15% of patients whose tumors are driven by certain gene fusions, there are drugs approved for use in the USA. Half of these patients have tumors driven by a fusion between the gene EGFR and several other genes. This makes EGFR (epidermal growth factor receptor, a growth factor for some cancers) hyperactive. Other patients have a fusion of the genes FGFR (fibroblast growth factor receptor) and TACC (transforming acidic coiled-coil), first reported in 2012 by the COlumbia University team.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minuteable now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

References: Nature Genetics (05 August 2013)

Erlotinib targeted therapy approved for metastatic lung cancer

Metastatic lung cancer is cancer that originated in the lungs and has spread to distant organs. It tends to go wherever the blood goes, including the liver, the bones, elsewhere in the lungs, and the brain. It is, alas, not curable. Still, chemotherapy and targeted therapies offer the possibility of improved quality of life, and can lengthen life as well. Hot off the press is news that the US FDA has approved a targeted therapy (erlotinib, also known as Tarceva) for the treatment of patients whose cancers have spread and who in addition have tumors that have something known as an epidermal growth factor receptor EGFR) mutation. Let’s take a closer look at this fascinating EGFR protein. There is a family of glycoproteins that poke out of the cell surface like antennae. We call them HER1, HER2, HER3, and HER4. In some patients with lung cancer, the HER1 is over expressed; there are too many of them. When the growth signal hits the EGFR receptor, it causes it to join arms with other HER family members, fueling the growth of the cell. Erlotinib (a pill) targets the EGFR.

On May 14, 2013, the US Food and Drug Administration (FDA) approved the use of a drug that targets the EGFR receptor. Here’s why the FDA took the step: A randomized, multicenter trial compared erlotinib (86 patients) to the more commonly used combination of a platinum chemotherapy drug with another drug (we call this a platinum doublet). All patients had to have an EGFR mutation.

The majority of the patients were female (72%), Caucasian (99%), never-smokers (69%), and had adenocarcinoma histology (93%). The median progression free survival (half of patients had progression by this point, half did not) was 5.2 months in the platinum doublet chemotherapy arm, and 10.4 months in the erlotinib arm. And the survival was a bit better with erlotinib, too: 22.9 months versus 19.5 months. The majority of the patients in the platinum-based chemotherapy arm (82%) subsequently received an EGFR tyrosine kinase inhibitor following investigator-determined disease progression.

What’s the downside of erlotinib? The most frequent (greater than or equal to 30%) adverse reactions of any grade in the erlotinib arm were rash, diarrhea, asthenia, cough, dyspnea and decreased appetite. The most frequent (greater than or equal to 5%) grade 3-4 (bad) adverse reactions in the erlotinib arm were rash and diarrhea. The recommended daily dose of erlotinib for NSCLC is 150 mg taken orally at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity.

Thank you for visiting. I’m Dr. Michael Hunter.

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Coming later this month: Understand Lung Cancer in 60 Minutes, an e-book for IPad.