Background
Precision Oncology has often been used interchangeably with two other related terms – Personalized Medicine and Targeted Medicine There is considerable overlap between these terms, although important distinctions exist as well.
All cancer is not the same. All patients are not the same. Should treatment be the same for all? The concept of Personalized Medicine is a reflection of this reality. Personalized treatments are tailored to the specific genetic and environmental factors of a particular patient with the goal of delivering the most effective care. Targeted Medicine and Precision Oncology can be considered specific offshoots of Personalized Medicine.
The discovery of “targetable mutations” heralded a new era of targeted oncology. The approval of Imatinib in 2001 for treatment of Chronic Myeloid Leukemia (CML) was a landmark event in this arena. Imatinib targets and inhibits a specific genetic alteration, the bcr/abl translocation, which is responsible for the growth and proliferation of CML cells. The use of Imatinib radically changed the natural history of CML from a fatal illness to a chronic disease. Many other drugs have made a substantial impact by targeting specific genetic alterations. Some examples include the use of Human Epidermal Growth Factor Receptor- 2 (HER-2) monoclonal antibodies for breast cancer, Epidermal Growth Factor Receptor (EGFR) inhibitors for lung cancer, and use of BRAF inhibitors for melanoma.
Precision Oncology takes the approach of personalized medicine to a new level of sophistication. The definition of Precision Oncology has evolved over the years. Although initially used to describe any form of targeted cancer treatment, in recent years, the term “Precision Oncology” is associated with treatments based on information derived from next-generation sequencing (NGS) of tumor tissue. Information gathered by analyzing genetic mutations in cancer cells can now be used to choose “precise” treatments directed at specific genetic alterations.
Despite the subtle differences highlighted above, there remains a significant overlap between the terms “personalized medicine,” “targeted oncology,” and “precision oncology.”
The current landscape of Personalized Oncology
The influence of personalized medicine is palpable in clinical oncology. Let us consider the example of Breast Oncology. For many years, a majority of patients with hormone receptor-positive breast cancer were treated with chemotherapy after surgery. Fortunately, we now have access to genomic assays that can determine if a patient’s cancer is likely to respond to chemotherapy. Today, many women can safely omit chemotherapy if they are determined to have a low-risk disease profile. Results of the TAILORx clinical trial were presented at the 2018 ASCO meeting in Chicago. This study showed that chemotherapy can be omitted in women older than 50 years with hormone receptor-positive, HER2-negative, node-negative breast cancer found to have “low risk” disease using the 21-tumor gene expression assay (Oncotype DX® Breast Recurrence Score). This study represents one the most impactful advances in the field of personalized medicine.
Patients with a type of breast cancer whose cells express HER-2 receptor benefit from HER-2 targeted therapies like Trastuzumab. Some patients who receive treatment before surgery experience responses so dramatic that cancer cells are undetectable at the time of surgery. This phenomenon is referred to as pathologic complete response (pCR). Patients who achieve pCR tend to have better outcomes than those who do not. In ER-positive/ HER-2 negative breast cancers, the CDK4/6 pathway plays a crucial role in causing resistance to traditional endocrine therapy approaches like Aromatase Inhibitors. In a series of landmark trials, the use of a new class of drugs called CDK4/6 inhibitors was shown to significantly increase the progression-free survival in patients with metastatic breast cancer.
We now know that genetic mutations that drive cancer growth can be acquired (somatic) or inherited (germline). BRCA 1 and 2 genes are well known inherited breast cancer genes. These genes, which can be inherited from either parent, increase the risk of breast cancer and ovarian cancer, among others. Genetic testing for BRCA genes is offered to healthy family members of patients with BRCA associated Breast cancer. When healthy women who are found to have BRCA gene mutation, personalized prevention strategies can be designed to reduce the risk of breast and ovarian cancer. In patients who develop germline BRCA gene-related cancer, a new class of drugs called PARP inhibitors is now approved for use.
Regulatory approvals- A new era for Precision Oncology
In 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab immunotherapy for treatment of patients with advanced cancer that harbor a genetic trait called microsatellite instability (MSI-high) or mismatch repair deficiency (dMMR). Patients with MSI-high tumors are now able to receive Pembrolizumab irrespective of the site of disease. This development marks a new era for the field of Precision Oncology. It is plausible that in the future, many cancer treatments will be approved based on genetic driver mutations rather than the site of disease.
Easy access to technologies for next-generation sequencing (NGS) will be critical for the widespread adoption of Precision Oncology. There are many commercially available assays for genetic analysis of tumors using NGS. In 2018, one of these assays received the first-ever FDA approval in this space. In the coming years, additional approvals in the area of diagnostic testing are likely. Sometimes physicians encounter logistical challenges to obtaining tumor samples to carry out NGS. A relatively new technology called “Liquid biopsy” holds tremendous potential for providing NGS data using a blood sample. Since tumor tissues shed DNA in the blood, “Liquid biopsy” can capture this information and provide actionable genetic information. Though relatively recent, “liquid biopsy” is already being used in clinical practice to diagnose specific mutations in cancer cells and to monitor response to treatment.
Precision Oncology: The hope, the hype, and reality
The success of Precision Oncology has not been without challenges and setbacks. The concept of precision oncology is based on the premise that all cancers are driven by precise, targetable genetic alterations. In an ideal world, these alterations would be identified and targeted with the available technologies. Unfortunately, at this time, only a small percentage of the genetic information obtained from NGS assays is truly “usable” or “actionable.” Many times, the significance of test results is not known. There have been reports of cases where an incorrect interpretation of NGS test results led to unnecessary treatment, anxiety or other adverse outcomes. Often when “precision treatments” are implemented, cancer cells may not respond very well or may respond for short periods of time before developing resistance mechanisms. Since the narrative of success is often dominated by few “super-responders,” it is true that sometimes the hype of precision medicine does not translate to reality for all patients. Clearly, there is a long road ahead. However, it is unmistakable that Precision Oncology is set to play a pivotal role in the goal of defeating cancer. The prospect of success is real!
References:
2018 ASCO: TAILORx: Most Women With Early-Stage Breast …. http://www.ascopost.com/News/58904
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