Cancer Mutations and Personalized Therapy

Is a revolution in treatment of cancer underway?  Scientists are looking forward to an era of personalized therapy for cancer patients. 

Also called genomic, genetic, and precision medicine, this paradigm involves doctors choosing treatment regimens based on genetic sequencing of each patient’s cancer.   Knowing the tumor’s genome can help physicians choose the best treatment. Indeed, one key to personalized therapy is rapid DNA sequencing which has become available only in recent years.  In addition, sometimes experiments are done on tissue removed from the cancer patients – it’s like a little clinical trial on just one patient.

The ability to determine which tumors have specific mutations and then test those cancers against drugs lets scientists figure out which drugs best treat which types of cancer. So while in the past, all cases of  adenocarcinoma of the lung cancer patients at the same stage might have been treated the same way, in the future, patients will get treatments that depend on the genotype of their cancer.

The new approach could be good news for cancer patients, doctors and drug manufacturers. Clinical trials for targeted therapy drugs usually require fewer test subjects and can be conducted at a much lower cost than trials for drugs aimed at a larger patient pool. These are sometimes called basket clinical trials.  The speed and efficiency of these trials allows doctors to obtain drugs faster and helps patients affected by a particular type of cancer with a peculiar biomarker can get the drugs that they need to survive that much sooner.

The results of the genomic analysis may suggest a course of treatment significantly different from traditional therapy and even end up with a different classification of disease.

The rollout of personalized medicine, if it happens, will be facilitated by new technologies, which is why observers are looking to use of blockchain and artificial intelligence, and general greater use of analytics to be important.  Personalization can apply to many areas but observers estimated that about 30 percent of the research in this field is in oncology.

The Mutations

Researchers and clinicians refer to cancer mutations by acronyms typically of 3 to 5 characters. For instance epidermal growth factor receptor is referred to as EGFR, and a mutation of this gene is of interest to lung cancer researchers. HER2 stands for human epidermal growth factor receptor 2, and it is a marker for some breast cancers.  Researchers at MD Anderson have proposed a Bayesian technique for efficiently choosing treatment.

Three quarters of lung cancer patients with EGFR-activating mutations respond well to the chemotherapy drug gefitinib. EGFR is a protein that cells produce, and improper activation can lead to uncontrolled cell division and cancer. The ALK mutation has been shown to respond to crizotinib in testing.  A study found that non-small cell lung cancer patients who took crizotinib along with their regular chemotherapy treatments saw their tumors reduced and survived four times as long as those on conventional chemotherapy alone.

Looking for biomarkers

Biomarkers are just chemicals in the body (blood or tissue) that indicate a physiological state; this state could include normal or abnormal function or a disease.  When you get a physical and they measure your cholesterol level, the cholesterol number is a biomarker.

During the diagnosis of cancer and when making decisions about treatment, doctors may look for biomarkers in the patient to identify the nature of the cancer, its state, and whether the body is responding to treatment.  The biomarkers are sometimes called molecular markers, and increasingly the biomarkers used to characterize cancer are evidence of specific mutations.

A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule.

When genetic biomarkers are employed to guide treatment decisions in cancer cases a sample from the patient is sent to a lab for analysis.  These tests cannot be done in a standard lab that produces a blood panel.  The lab looks at malignant cells and healthy ones and identifies genetic changes in the tumor that can be exploited with targeted drug therapy.

Tumor-agnostic treatments

The FDA’s approval of the immunotherapy Keytruda in 2017 was heralded as first treatment “based on the genetic characteristic of tumors, rather than their location in the body.”

See our page on tumor-agnostic drugs.

Theranostics is an exciting area of research that may produce useful treatments.  The idea is that paired therapy and diagnostic tests could reduce delays in treatment by eliminating steps.

Targeting Mutations

The National Cancer Institute has created the Lung Cancer Mutation Consortium of more than 20 major cancer research and treatment centers across the country. The consortium is a coordinated effort to find a quick assay for identification of tumor mutations including KRAS, HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS, and MET.

Drug researchers are already working on compounds that will treat cancer with these mutations in various cancers. The HER2 mutation is already a target of two breast cancer drugs on the market – Trastuzumab and Pertuzumab.

doctor with cancer patientEarly results show that show that 54% of the tumors tested under consortium auspices have single-driver mutations. Tumors with only one mutation may turn out to be more amenable to treatment.

There are skeptics who point out that even when a patient’s cancer is sequenced, doctors are not usually able to pair the patient with a regimen that does significantly better than the old-style treatment.

Other scientists look to a future of personalized therapy in which the chemotherapy regimen is chosen based partly on genetic tests of the tumor. This change has been made possible partly by technological advances in genome sequencing. Using therapies that are known to be effective against specific mutations, doctors can raise the odds of success. The one-size-fits-all treatment, which does not take into account the tumor mutation, is most often used today, but if this revolution goes forward as many suspect, it will be seen in the future as primitive.

The personalization of treatment is not only a grail for many cancer researchers, but remains the best hope of ensuring that increasingly expensive treatments are affordable to society. At present there is no form of cancer for which cancer vaccines are the standard therapy or any part of the standard therapy, but there is much exciting research and trials going on.

A 2018 study by Oregon Health & Science University researchers estimated that 4.9 percent of US cancer patients could benefit from genomic therapy.

Custom Dosing

Another way to personalize treatment is to more closely adjust chemotherapy dosing so that it is appropriate for the patient.  Traditionally this has been done by considering the patient’s body surface area (for cytotoxic drugs) or weight (for monoclonal antibodies).

It is conceivable that more precise dosing could be based on pharmacogenetics and pharmacokinetics.

See also: adaptive chemotherapy

Genome-driven treatment schemes.