Cancer specialists have always had the goal of «precision» to accurately diagnose a cancer, use surgery to remove cancerous tissue, or use medicines and radiation to kill cancer cells without harming surrounding tissue and organs. With recent advances in more powerful ways to see and understand a person’s genetic and tumor makeup at the molecular level, precision in oncology has come to mean more specifically the diagnosis, treatment, and ongoing management of cancer based on a person’s unique molecular and genetic patterns.
The NCI defines precision medicine as «a form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease. In cancer, precision medicine uses specific information about a person’s tumor to help make a diagnosis, plan treatment, find out how well treatment is working, or make a prognosis or forecast of how things are likely to go.» (Ref: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/precision-medicine).
Precision has always been the goal of cancer specialists, but with recent advances in more powerful ways to see and understand a person’s genetic makeup and cancer at the molecular level, plus the discovery of anti-cancer agents to interfere with cancer’s machinery, precision in oncology has come to mean more specifically the diagnosis, treatment, and ongoing management of cancer based on what the molecular and genetic signals are telling the treating physician.
Precision diagnosis is what underpins the practice of precision oncology and is generally referred to as the molecular, genetic, or biomarker testing whereby a specialized test or series of tests can identify distinctive genetic and molecular patterns influencing how a person’s cancer tumor forms, grows, and survives. The ability to manipulate this biology with advanced medicines is at the heart of precision oncology as qualified physicians identify patients diagnosed with cancer who may benefit from one or more treatments based on the molecular profile of their cancer. Aspects of this molecular and genetic profile are also referred to as biomarkers or driver mutations. It is also becoming increasingly possible for sophisticated genetic and molecular testing to pick up signals of cancer development prior to an official diagnosis. For instance, recent research showed that for a subset of patients eventually diagnosed with head and neck cancer caused by HPV16, circulating tumor DNA in plasma samples was identifiable months and years prior to diagnosis (Ref: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.33996).
Precision treatment includes a variety of currently approved anti-cancer therapies and many more in clinical research that technically fall within the parameters of precision oncology. Here are a few broad categories that more or less cover the spectrum of precision oncology treatments.
One category is targeted cancer therapy which refers to a cancer’s molecular profile revealing a specific «target» that might then be matched to a known therapy. Examples abound for example in lung or breast cancer where specialists have discovered a variety of molecular-driven subtypes of disease and how they might be treated and sometimes just as importantly how they should not be treated. The targeted therapies in this category are for the most part either small molecule drugs or monoclonal antibodies and some have been found to work well in more than one cancer. Generally, targeted therapies are best identified by the specific type of cancer they were designed to treat. The US National Cancer Institute (of the National Institutes of Health) maintains a current list of what they consider approved targeted cancer therapies organized by cancer type at https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/approved-drug-list.
There are estimates that 60 percent or more of advanced lung cancer cases may benefit from targeted therapy with FDA-approved precision medicines for advanced lung cancer driven by the biomarkers EGFR, ALK, ROS1, MET, RET gene alterations, and KRAS. Other biomarkers in lung cancer are being heavily investigated as potential targets. (Ref from big paper). Another set of targeted therapies called PARP inhibitors have been shown to help fight cancers with BRCA mutations that increase a person’s risk of developing breast and ovarian cancer. These medicines work by interrupting the DNA repair process used by cancer cells to multiply and are FDA-approved as therapies used after chemotherapy to prevent or delay cancer recurrence. Cancer specialists are testing whether these inhibitors might also work alone or in combination with other medicines in cancers not driven by the BRCA mutation. (Ref: Nature paper what’s next for PARP inhibitors at https://www.nature.com/articles/d41586-021-03714-w.)
A second broad category of precision oncology treatments is known as cancer immunotherapy that harnesses the power of the human immune system to fight cancer. There are many different types. For example, some monoclonal antibodies are specifically designed to help the immune system to recognize and attack cancer cells. In fact, specialists are now combining monoclonal antibodies into what are called bispecific antibodies that can attach to two different cellular targets at the same time. Only a few are currently FDA-approved, but there are several hundred in the development pipeline (Ref: https://www.onclive.com/view/bispecific-antibodies-could-be-the-next-big-advance-in-oncology). Cancer treatment vaccines work in a similar way to prime the immune system to recognize and kill cancerous cells. Messenger RNA (mRNA) vaccines proven effective in Covid-19 are beginning to show their clinical promise in cancer and are custom made for every individual. Immuno-modulating drugs strengthen key parts of the immune system by increasing the number of white blood cells for instance, or help protect patients from the worst side effects of treatment by stimulating red blood cell growth. Angiogenesis inhibitors are utilized to restrict a cancer’s ability to grow new blood vessels, depriving a tumor of needed sustenance. A weak version of the virus that causes tuberculosis is used to stimulate an immune response in bladder cancer and is being studied for other cancers, too.
Perhaps the more notorious immunotherapy agents in cancer today are immune checkpoint inhibitors designed to frustrate how cancer cells trick the immune system into not attacking. These inhibitors are the first FDA-approved tissue-agnostic or pan-tumor cancer agents meaning their clinical utility is determined by tumor molecular behavior and not by location in the body. Thus, the list of cancers susceptible to checkpoint inhibition is large and still growing as clinical research continues apace. Finally, cancer immunotherapy includes immune cell therapy (for example, CAR-T) whereby a patient’s immune cells are isolated in a lab, reengineered, and then reinfused in great amounts and with a greater ability to recognize and fight cancer. Thus far, cell therapies are FDA-approved for blood cancers but are still experimental in solid tumors.
While targeted therapy and immunotherapy in cancer generally covers the gamut of PMO treatments, there are some others that do not fit squarely into either of these categories but are still considered forms of precision. For instance, anti-cancer therapies that leverage a tumor’s reliance on hormones–called hormone therapy used in prostate and breast cancer–are utilized alone or in combination with other targeted treatments in some patients but not in others. Some hormone treatments are even approved to prevent cancer in persons determined via family history and genetic screening to be at high risk of developing breast cancer.
Another emerging type of precision that does not fit squarely into any broad categorization are antibody–drug conjugates (ADCs). These anti-cancer medicines combine three elements to deliver a cytotoxic agent directly to cancerous cells. The three elements are an antibody (like a monoclonal antibody), the cytotixic agent (like a chemotherapy), and a mechanism to bind the two. The antibody directs the medicine to attach to specific target cancer cells. Once bound, the cytotoxic agent, sometimes called the «payload,» is released directly into the cells causing cell death or otherwise interrupting the cancer cell’s internal machinery. The route of administration is infusion in a clinical setting. Many ADCs are particularly powerful in treatment-refractory disease where other options have been tried but nothing has worked. Nonetheless, scientists are still working to understand what happens with ADCs in the body so widespread use of these medicines is still limited. A list of the 11 FDA-approved ADCs as of September 2021 is available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510272/pdf/molecules-26-05847.pdf. Eight of the 11 are since 2017. The pipeline of pre-clinical and clinical studies of ADCs is tremendously full – about 80 in development. Currently, ADCs are used in certain types of leukemia, lymphoma, multiple myeloma, breast cancer, cervical cancer, and urothelial cancer.
See also https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287784/pdf/nihms-1714939.pdf
https://www.mdpi.com/1420-3049/26/10/2943
https://www.astrazeneca.com/our-therapy-areas/oncology/antibody-drug-conjugates.html
Precision in Ongoing Management
When cancer specialists run molecular tests to determine if a cancer remains in remission, has returned, and/or requires a new or different approach, they are practicing precision as ongoing cancer management. Different tests can be performed to tell if a tumor has become resistant to treatment, is still growing, how fast or aggressive it is, and if and how the prognosis has changed for that patient over time. When these tests are run, specialists are looking for what they call tumor markers, which is anything in the body produced by or related to cancerous cells. In fact, many of these tests are the same ones used to determine if a patient could benefit from a targeted therapy, thus it is not unusual to have multiple molecular or genetic tests for the same patient over a period of time as things change. The NCI maintains a list of tumor markers that are tested for including for which types of cancer and how they are utilized in ongoing management at https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-list.
