Is It Not Time for More Precise Medicine? Cancer and Precision Medicine

The History of Cancer goes back even further than human history. The oldest known evidence of cancer in humans was found in fossilized bone tumors during analyses of Egyptian mummies. Humanity had to wait until the 19th century for studies aimed at understanding cancer mechanisms; the visualization of cancer cells under the microscope beginning in 1845 opened the door to modern cancer treatments. Although cancer has such an ancient history, developing treatment strategies at molecular and cellular levels is very recent.

Although oncology has developed rapidly under the influence of other scientific disciplines, a single drug capable of treating all cancers has not yet been discovered. This is because cancer is a heterogeneous (mixed) group of diseases. In other words, cancer cells vary from patient to patient, and even in the same patient it is possible to encounter cancer cells with different genetic structures. Therefore, a one-size-fits-all approach to cancer treatment is not possible. In recent years, with advances in genetics , cancer treatment has seen precision medicine (precision medicine & oncology) begin to gain importance. Previously, terms such as personal, individualized or personalized treatment were used instead of precision medicine. However, the discovery that even within the same person the genetic structure and consequently biological behavior of cancer cells may differ demonstrated the need for more precise approaches. Thus, based on the principle of analyzing genetic differences at the cellular level, precision medicine was born.

Precision medicine seeks the most appropriate and effective treatment based on the genetic structure of the patient and their cancer

The extent to which precision medicine can provide clinical benefit is frequently debated. There is evidence that precision medicine can be used effectively in cancer treatment. This includes:

1. More Patients Benefiting from Precision Medicine Compared with Conventional Chemotherapy

Survival has been greatly extended in some cancer patients receiving targeted treatment. For example, the Bcr-abl gene fusion (a type of mutation) enabled the development of a targeted drug. The drug imatinib, targeting BCR-ABL, increased survival in chronic myeloid leukemia patients at 5 years by 90 percent and at 8 years by 88 percent. Treatment developed against this genetic abnormality, found in almost all chronic myeloid leukemia patients, is a result of “precision medicine.” Another example is HER2-positive breast cancers, against which drugs such as trastuzumab, lapatinib and pertuzumab were developed.

Using trastuzumab (Herceptin) with conventional chemotherapy reduced the risk of death by 20 percent. It also slowed disease progression and significantly increased survival.

2. Precision Medicine Offers New Treatment Strategies Suited to the Genetic Structure of Cancer

Precision medicine also aims to identify cancer’s weak points and use medicines appropriate to these weaknesses. Synthetic Lethality (synthetic lethality) is one of the most important strategies targeting a weak point of cancer. This strategy is fundamentally based on gene interactions. For example, simultaneous inactivation of two or more genes in a cancer cell triggers cell death, while inactivation of only one of these genes supports its survival. Researchers try to develop medicines by identifying such interacting genes. In 2005, such a relationship was identified between the BRCA gene and poly ADP ribose polymerase (PARP) genes. In 2014, the United States Food and Drug Administration FDAapproved the use of the PARP inhibitor Olaparib in ovarian cancer patients with BRCA mutations.

To explain this simply, BRCA and PARP genes are involved in repairing DNA damage. If only one of these genes is defective, the cancer cell continues to live. However, if both are disrupted, the cancer cell cannot effectively repair DNA. Researchers succeeded in destroying cancer cells by targeting the PARP gene in patients with a defective BRCA gene. Genes with similar relationships are currently being discovered and medicines developed. One of the important proteins supporting cancer cell growth ismyc. Drugs developed against these proteins are now being tested in phase-1 clinical trials .

3. Precision Medicine Uses the Latest Genetic Engineering Technologies

Precision medicine works in coordination with genetics. With crispr , one of the revolutionary genetic engineering technologies, desired changes can be made in DNA, allowing mutations in a patient’s cancer cell to be reproduced. This greatly facilitates new drug development. In addition, CRISPR/CAS9 genetic technology can modify immune system cells and program them to attack the patient’s cancer cells more effectively. Clinical trials have begun in different cancer types.

Another new technology used in precision medicine is Cryo-Electron Microscopy. This method enables proteins and similar molecules to be examined by freezing them. In this way, responses to medicines and mutations in the patient can be seen more clearly.

What Problems Are Encountered in Precision Medicine?

• Considering all cancer types, the greatest obstacle facing precision medicine is that the rate of identifying a meaningful genetic mutation that can currently be targeted remains only %30-40. Moreover, even if certain mutations are found in the tumor, it must be clarified whether they are also present in normal tissue (this comparison cannot currently be made because normal tissue is not biopsied in routine practice). In addition, targeted drugs have not been developed for every mutation.
• The other two major challenges are accessibility and cost. Genetic tests are needed before targeted medicines can be administered. However, genetic testing is currently expensive. Tests must also be performed at a good center to ensure reliability. In addition, the high prices of targeted medicines make it difficult to deliver them to patients.
• Criticisms of precision medicine also include shortcomings in clinical research. Difficulty accessing targeted medicines and an inability to obtain certain tumor samples lead to clinical trials with few participants. To overcome these problems, new clinical trial designs have begun to be defined:
  1. In the system called NCI-MATCH, patients enter clinical trials with treatment selected according to their genetic structure rather than tumor histology (microscopic appearance). The absence of a control group is a major shortcoming of this design.
  2. NCI-MPACT targets driver mutations. Patients with advanced cancer and genetic abnormalities in any of the cellular pathways such as DNA repair, PI3-K/mTOR and Ras/Raf/MEK enter these clinical trials. Patients without a driver mutation are not included.

It is important to emphasize that the fundamental cause of cancer is gene damage. This gene damage varies from patient to patient and even between different organs in the same patient. Precision medicine, which seeks to plan treatment by identifying these differences, will form the fundamental principle of cancer treatment in the future.

In the figure below, methods used in molecular genetic-based tests are shown schematically.