Clinical Biomarkers Are the Key to Precision Medicine in Prostate Cancer

A biomarker is an objective indicator in the body that corresponds with the status of a specific health condition.¹ Biomarkers can indicate the presence or progression of a condition and can provide insight into how a condition responds to treatment. In 2015, a joint leadership council between the FDA and the National Institutes of Health created the Biomarkers, Endpoints and other Tools (BEST) Resource, which defined 7 biomarker categories, including susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety.²

Historically, patients with a particular cancer type all received the same treatment, including cytotoxic chemotherapy and/or radiation that attacks the cancer cells but also damages healthy tissue in the process. Research over the years has shown genetics, inherited or acquired, can impact the risk for developing cancer, the prognosis following a cancer diagnosis, and even the tumors themselves. Genetic factors relate to unique features within tumors even of the same cancer types. Current treatment approaches increasingly rely on cancer biomarkers to gain information about a patient's cancer to predict which treatment may work best for them, a practice known as precision medicine. At a fundamental level, precision medicine focuses on selecting the right treatment, for the right patient, at the right time to optimize health outcomes.³ Precision medicine looks at genetics, the environment, and lifestyle of a patient and accounts for specific information about the cancerous tumor to aide in diagnosis, estimate prognosis, select therapy, and monitor the efficacy of treatment.

Benefits of precision medicine include enhanced patient safety and improved outcomes. Through enhanced screening protocols and measurement of biomarkers, patients at risk may be identified sooner and disease detected earlier. Furthermore, patients undergoing treatment are living longer without disease recurrence or progression and with fewer adverse effects, resulting in preservation of quality of life.

Types of Biomarkers in Prostate Cancer

Clinically relevant biomarkers can be grouped into 2 types, germline genetic markers and tumor markers. Germline genetic markers are collected from the DNA of healthy cells to identify inherited gene mutations.⁴ Germline testing is typically performed at the time of cancer diagnosis to identify whether any deleterious variants (genes linked to hereditary cancer syndromes and/or impacting prognosis and treatment response) exist. Germline genetic markers relevant in prostate cancer include BRCA1, BRCA2, ATM, PALB2, CHEK2 [DNA repair genes], HOXB13, MLH1, MSH2, MSH6, and PMS2 [DNA mismatch repair genes].⁵ These markers serve to guide treatment approach, management of other hereditary cancers, and provide insight into potential surveillance protocols for at-risk family members. BRCA1/2 is associated with earlier cancer diagnosis, more aggressive phenotype, increased risk or progression on local therapy and decreased overall survival (OS). MLH1, MSH2, MSH6, and PMS2 are associated with an increased risk of prostate cancer and may infer susceptibility to pembrolizumab (Keytruda; Merck & Co) in later lines of therapy. HOXB13 primarily informs family counseling.

While germline testing looks at the genetics of the patient, tumor markers are specific to the cancer itself. Tumor markers are divided into 2 types, circulating tumor markers (CTMs) and tumor tissue markers (TTMs). CTMs are defined as "substances found at higher than normal levels in the blood, urine, stool or other bodily fluids in some people with cancer." This type of biomarker must always be accompanied by additional testing, such as biopsy or imaging since elevated CTMs are not specific to cancer. This means that patients without cancer can still have elevated levels and not all patients with cancer will have high levels. A common CTM relevant in prostate cancer is prostate specific antigen (PSA), which is a substance made by the prostate and is often elevated in men with prostate cancer.6 As is common with CTMs, PSA is not specific to cancer and may be elevated in other conditions (certain medical procedures, medications, or an enlarged or infected prostate) therefore biopsy is needed to determine the presence of cancer. PSA also plays a role in monitoring disease status following a PC diagnosis through assessment of PSA doubling time. PSA doubling time estimates the number of months it would take for the PSA to double and serves as a validated indicator of biochemical and clinical progression.⁷ Simply put, the shorter the PSA doubling time, generally the worse the prognosis for the patient.

TTMs encompass characteristics and genetic makeup of the tumor cell itself. These may include surface receptors or proteins on or inside tumor cells that can be targeted with pharmacologic therapies. Examples in prostate cancer include alterations in homologous recombination DNA repair genes such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12.⁵ In metastatic prostate cancer (mPC), alterations in these genes may be predictive of clinical benefit of poly-ADP ribose polymerase (PARP) inhibitors and may infer sensitivity to platinum agents; however, further research is needed. In the castration-resistant (mCRPC) setting, these patients may have better responses to hormonal therapies like enzalutamide (Xtandi; Astellas Pharma and Pfizer) and abiraterone (Zytiga; Janssen Biotech) as opposed to taxanes. CDK12 mutations tend to be associated with more aggressive disease with higher rates of metastasis and shortened OS, as well as lower response to hormonal therapies, PARP inhibitors and taxanes. A more recently identified TTM that holds value in guiding therapy selection in mCRPC after failure of abiraterone and enzalutamide is androgen receptor splice variant 7 (AR-V7). TTMs can also be identified gene mutations that affect cancer growth, often referred to as "driver mutations." BRCA1/2 is an established driver mutation in PC associated with poorer prognosis, but is typically susceptible to targeted therapy with PARP inhibitors.

In metastatic prostate cancer (mPC), alterations in these genes may be predictive of clinical benefit of poly-ADP ribose polymerase (PARP) inhibitors and may infer sensitivity to platinum agents; however, further research is needed. Image Credit: © Dr_Microbe - stock.adobe.com

Implications of Prostate Cancer Biomarkers

Clinical biomarkers largely impact a patient's journey through cancer care. Germline mutations in DNA repair genes such as BRCA1, BRCA2, ATM, PALB2, CHEK2, and HOXB13, and DNA mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2 aid in the identification of overall risk for developing prostate cancer and inform counseling and screening protocols for family members. Furthermore, germline mutations such as BRCA1/2 along with CTMs such as PSA and TTMs such as CDK12 can be used to estimate prognosis or risk for disease recurrence following a prostate cancer diagnosis. Most notably, these biomarkers all aim to inform treatment decision making, aiding in the selection of certain therapeutic approaches and in monitoring disease status and response to treatment.

Biomarkers inform clinicians about a patient's disease and are increasingly used to guide therapy. The realm of clinically relevant biomarkers is continuously evolving as research aims to enhance a tailored approach to treatment and ultimately improve patient outcomes.

REFERENCES

1. Role of Biomarkers. CancerCare. Accessed October 20, 2023. https://www.cancercare.org/publications/413-understanding_the_role_of_biomarkers_in_treating_cancer
2. About Biomarkers and Qualification. FDA. July 7, 2021. Accessed October 20, 2023. https://www.fda.gov/drugs/biomarker-qualification-program/about-biomarkers-and-qualification
3. What is precision medicine? Medlineplus.gov. Accessed October 20, 2023. https://medlineplus.gov/genetics/understanding/precisionmedicine/definition/
4. Indications for germline testing in cancer patients. The Jackson Laboratory. Accessed October 20, 2023. https://www.jax.org/education-and-learning/clinical-and-continuing-education/clinical-topics/tumor-testing/germlinetest
5. National Comprehensive Cancer Network. Prostate Cancer (Version 4.2023). Accessed October 20, 2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
6. CDC Prostate Cancer. What is screening for prostate cancer? Centers for Disease Control and Prevention. July 19, 2023. Accessed October 20, 2023. https://www.cdc.gov/cancer/prostate/basic_info/screening.htm
7. Vickers AJ, Brewster SF. PSA velocity and doubling time in diagnosis and prognosis of prostate cancer. Br J Med Surg Urol. 2012;5(4):162-168. doi:10.1016/j.bjmsu.2011.08.006