Introduction
Cancer is one of the leading causes of death worldwide and carries a heavy burden and cost. Our increased understanding of molecular biology is leading to not only new cancer treatment options but new treatment paradigms. As we better understand the root cause of genetic alterations, new molecular targets and therefore targeted therapies emerge that are independent of cancer origin and location. Traditional therapies and guidelines previously focused on cancer location; however, in this new era of understanding, it is apparent we need new rules. Treatment protocols and guidelines must be established based on molecular abnormalities irrespective of the original cancer site, and payers must recognize the need and benefits of these in order to address patient and societal needs.
Pathophysiology and Current Treatment of Cancer
Cancer occurs when genetic alterations within a cell lead to inappropriate cellular replication, survival, and avoidance of the immune system.1,2 For example, during normal development, genes responsible for cell proliferation and migration are necessarily “on” during the process, then “turned off” once the process is complete. Cells with genetic alterations in this process can lead to erroneous activation or inactivation of these genes,3 ultimately leading to uncontrolled proliferation (cellular division) and migration (metastasis), 2 classic hallmarks of cancer.
Cancer can occur almost anywhere in the body1 and, historically, is largely classified by location and broad histology. This classification is also reflected in current treatment guidelines.
Traditional Cancer Therapies
Surgery to remove cancer was first documented in an ancient Egyptian text and became more common in the 1800s with the development of anesthesia.4 Radiation therapy in cancer treatment was pioneered in the early 1900s.5 These nonpharmacologic therapies are still important to remove or debulk tumors locally and often accompany pharmacologic approaches to achieve the overall treatment goals of remission and survival.6,7
Chemotherapeutics are historically the first form of pharmacologic intervention and generally target rapidly dividing cells, which include both cancerous and healthy cells.8,9 The death of healthy cells, such as those of the hair, skin, intestines, and bone marrow, results in several common adverse events with chemotherapy.10 Therefore, a delicate balance must be struck so that the death of healthy cells, and therefore potential adverse events, is minimized, while the death of cancer cells is maximized.
Emerging Therapeutics
The chemotherapy regimen selected has traditionally depended on multiple factors, including the histopathology and location of the cancer. However, advancements in precision medicine are changing how scientists and healthcare professionals (HCPs) think about treatments. Targeted therapies, tumor-agnostic treatments, and molecular testing empower HCPs to choose cancer treatments based on genetic and molecular features rather than tissue of origin or histology.11
Targeted Therapies in Oncology
Recently, novel cancer treatments have been realized based on an improved understanding of genetic mutations in cancer cells and the molecular pathways involved. Examples include therapies targeted toward the immune system (immunotherapies) or cellular growth and survival of cancer cells.8,12 Unlike traditional chemotherapy, which affects the cellular functions of all tissues, targeted therapies act on specific components or pathways associated with cancer cells. Thus, these therapies should preferentially inhibit cancer cell activities and be less toxic to healthy cells. However, targeted therapies can still have substantial adverse effects.10
| Table 1. Targeted Therapies in Cancer | ||
| Mechanism | Example therapy | |
| Immunotherapies | Immune checkpoints inhibitors (eg, PD-1, PD-L1, CTLA-4, LAG-3, CD40)13 | Ipilimumab, nivolumab, pembrolizumab, others in development13 |
| Antibodies to stimulate immune response14 | Bevacizumab, cetuximab, rituximab, trastuzumab14 | |
| Cellular therapies (eg, CAR T) | Idecabtagene vicleucel15 | |
| Molecular targets | Oncogene targets (eg, RET, ROS1, EGFR, VEGF)16 | Abemaciclib, entrectinib, fruquitinib, larotrectinib, selpercatinib16 |
| Targeted chemotherapies (eg, antibody-dependent cell-mediated cytotoxicity) | brentuximab vedotin14 | |
Immunotherapies
Immunotherapies (Table 1) are a group of treatments that support immune system recognition and subsequent destruction of cancer cells14 and/or help overcome treatment resistance. There are several ways to target the immune system to achieve these goals, including monoclonal antibodies (mAbs) to inhibit immune checkpoint proteins (immune checkpoint inhibitors) and cellular therapies that adapt a patient’s own cells to better fight cancer, among others.
Immune checkpoints regulate the immune system and are one of the ways the immune system recognizes self. Genetic abnormalities in cancer can modulate these checkpoints in order to avoid the immune system. Immune checkpoint inhibitors are widely used to help overcome immune system resistance13 and can bind to ligands (eg, PD-L1) or receptors (eg, PD-1) on the surface of cancer cells or T cells, respectively. In resistant cancer cells, ligand-receptor binding inactivates T cells, causing immune resistance. Immunotherapy blocks the ligand from binding the receptor, thus preventing resistance and allowing the activation of T cells and destruction of cancer cells.13
Adoptive cell transfer (ACT) is a new and emerging cellular therapy that involves collecting and modifying immune cells from the patient and using those cells to treat the cancer.17 Chimeric antigen receptor T-cell therapy (CAR T), a type of ACT, is where T cells from the patient are modified to express antibodies to the cancer cells. The first such therapy was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphoblastic leukemia in children and advanced lymphoma in adults.18 While CAR T is the first ACT to receive FDA approval, other types of ACTs are in development.
Molecular Targets
As genetic drivers of cancers are becoming better understood, new treatments directed toward those targets are being developed. Molecular targeted therapies are more precise and generally less toxic than conventional chemotherapy because they target specific biomarkers or pathways involved in the growth and spread of cancer (Table 1). These therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, mAbs that deliver cytotoxic drugs, and more.10,19
Protein kinases, particularly receptor tyrosine kinases, are critical enzymes in signaling pathways throughout the body and are often key to turning processes on and off. They influence complex molecular pathways involved in regulating cell growth, cell death, and vascular development. Mutation or dysregulation of these protein kinases at their genetic level can lead to cancer, making them ideal targets. Initial targeted therapies have focused on generalized cell growth and broader tyrosine kinases, which can lead to off-target effects and unwanted side effects of treatments. More specific kinase targets and targeted therapies are being developed with the aim of overcoming common toxicities seen with multikinase inhibitors.20
Another targeted treatment approach is through antibody-drug conjugates (ADCs), where antibodies target molecules specifically expressed in certain cancers to deliver cytotoxic drugs to those cancer cells. The first ADC was approved in 2001, and, as of May 2021, 10 more received FDA approval with exclusively oncology indications. There are currently 80 ADCs under active clinical development.21,22
While molecular targeted therapy is a breakthrough in cancer treatment, limitations remain as the treatment only works in patients with a particular biomarker, and/or resistance may develop as cancer cells further mutate to bypass the affected molecule or molecular pathway. Therefore, the current treatment approach is to combine targeted therapies with other therapies to destroy cancer cells more effectively. However, the molecular targeted therapy approach has laid the foundation for the development of precision medicine as the new paradigm.19
Changing Paradigm in Cancer Treatment
Evolution of Cancer Treatments and Precision Medicine
As our understanding grows, we are realizing the traditional focus on cancer location and histology to select treatment protocols may not always provide optimal patient outcomes, and valuable time and resources may be spent on nonresponders. In contrast, precision medicine holds promise for efficiency as it allows for better allocation of resources by preemptively prescribing a treatment based on the genetic and molecular profiles of the cancer.11
As targeted therapies are directed at genetic mutations, companion diagnostics are an essential tool to select appropriate therapies.10 Currently, there are more than 20 cleared or approved companion diagnostic tests, the majority of which are associated with various cancer treatments that target specific mutations.23 It has been noted that patients who receive companion diagnostic testing coupled with biomarker-driven treatment show substantial survival benefits, and national and international guidelines recommend companion diagnostic testing in these patients. Despite this, the adoption of precision medicine into clinical practice has been slow,24 and many patients still do not receive molecular testing.19
In response to these changes, clinical trials are also evolving with the introduction of basket trials, which group cancers in clinical trials together by their genomic alteration rather than location. These trials can broaden the target patient population and include rare cancers that are often underrepresented in clinical trials.25 Indeed, basket trials were successfully used to support approval for tumor-agnostic indications for pembrolizumab in 2017,26 and more recently for larotrectinib27–30 and entrectinib.31-33
As the genomic characterization of tumors and treatment selection based on specific molecular biomarkers become more comprehensive and complex, the need for efficient and rigorous approaches to investigate prospective therapies for cancers based on their genomic alterations rather than their site of origin will be critical.25
Paradigm Shift
As our understanding and treatment options are expanding at record paces, the complexity of diagnosis and treatment is also increasing, making it more difficult for clinicians to keep up with the latest standards. Access to resources is often limited by socioeconomic status, insurance coverage, and site of cancer care. Many physicians do not have access to testing resources or may lack training to interpret the results. Even when physicians do have access to companion diagnostic tests, cost may be an additional barrier. Molecular testing results may indicate expensive targeted therapies that fall outside of the standard of care for that cancer type and may not be covered by insurance.11
In addition to these barriers, as advancements in personalized medicine move at a rapid pace, clinical guidelines struggle to keep up, which presents challenges in integrating personalized medicine into common practice.24 For example, even though National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology increasingly include biomarker testing and focus on personalized treatment, they continue to encourage a traditional approach to treatment simply by how the cancers are organized within the guidelines.34
Physicians may also intentionally forego molecular testing and a potential delay in treatment initiation in favor of traditional therapy based on the location and histology. Therefore, HCP training on updated guideline recommendations and the importance of proper diagnosis with the use of companion diagnostics will be key. Furthermore, simplified diagnostic and treatment algorithms can help HCPs identify the ideal approaches for their patients.
As we learn more about the molecular pathways involved in cancer, it becomes apparent that the guidelines and standards of care must evolve along with the diagnostic and treatment landscape. Diagnostic and treatment protocols and guidelines must be established based on these targeted therapies irrespective of the original cancer site. Physicians and other HCPs treating patients need education on the multitude of emerging diagnostic and treatment options. Simplified clinical maps are needed to assure clinicians use and interpret the information to optimize patient outcomes, and payers must recognize the need and benefits of these in order to address patient and societal needs.
References
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