Episode 63 - Tumor Markers Basics - a podcast by Rio Bravo Family Medicine Residency Program

Episode 63: Tumor Markers Basics. 

George and Harendra discuss with Dr Arreaza the role of tumor markers in the diagnosis and monitoring of different types of cancer.  

Introduction: Recent News about COVID-19
Written by Hector Arreaza, MD. Participation: George Karaghossian, MS3, and Harendra Ipalawatte, MS3.

Before we talk about our topic today, there are three news worth sharing about COVID-19.

First, we are all aware of the increased number of patients affected by COVID-19 and increased mortality. Most of the patients who are severely ill or those who require admission are unvaccinated. The cases of breakthrough infections (infections in patients who are fully vaccinated) continues to be rare.

Second, CDC has officially recommended COVID-19 vaccination in pregnant women (August 11, 2021)[1].  All people 12 years of age and older is recommended to get vaccinated against COVID-19, including pregnant women. There were 2,500 women who received the mRNA vaccine against COVID-19, and there was not an increased risk for miscarriage. Vaccinated pregnant women (or persons) had a miscarriage rate of 13% (similar to the miscarriage average in general population, which is 11-16%).

Third, FDA gave an emergency use authorization for a third dose of mRNA vaccines (Pfizer and Moderna) for certain immunocompromised patients (August 12, 2021)[2]. The third dose of the vaccine (it has to be the same vaccine you received) has to be given at least 28 days apart from your last dose. Patients who may receive a third dose include: Patients who are undergoing active treatment for solid tumor and hematologic malignancies, recipients of solid-organ transplant and taking immunosuppressive therapy, moderate or severe primary immunodeficiency (e.g. DiGeorge syndrome, Wiskott-Aldrich syndrome), patients with advanced or untreated HIV infection, patient who are taking high-dose corticosteroids (i.e. >20 mg prednisone or equivalent per day) and other immunosuppressive medications. If in doubt, consult our oncologists and rheumatologists.

Let’s switch gear and introduce the topic for today. Given the high mortality and morbidity of cancer, in general, early detection of cancer is one of the most important goals in primary care. Today George and I will discuss the usefulness, pitfalls and will mention some of the most common tumor makers.

This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. 

Tumor Markers Basics. 
By George Karaghossian, MS3, Ross University School of Medicine; Harendra Ipalawatte, MS3, Ross University School of Medicine; and Hector Arreaza, MD.  

 

Introduction:
Do you remember how we came up with the idea for this topic? We had a patient with an intraabdominal malignancy which appeared to be from the GI tract vs an adnexal mass. We order tumor markers to assist in the diagnosis of the origin of this malignancy. 

 

Definition: Tumor markers are usually proteins or other substances that are produced by cancer cells or non-cancerous cells. Circulating biomarkers and tissue biomarkers are the two types of tumor markers we utilize to track the course of the tumor’s growth. Circulating tumor markers are found in bodily fluids such as blood, urine, and stool. Tissue markers are typically found on the actual cancer cells. These markers can help in the assessment of certain cancers. The downside of tumor markers is that they are not always reliable, and they may not be detected in the early stages of cancer[2]. 

 

Characteristics of a good screening test: A good screening test must be capable of detecting a high proportion of disease when patients are asymptomatic, tests should be safe, not excessively expensive, lead to improved health outcomes, be widely available, and interventions after a positive test should also be available.

 

Can tumor markers be used for cancer screening?
Tumor markers should not be used as a primary tool for cancer screening because they lack sensitivity and specificity. The most definitive tool for diagnosis of cancer therefore is biopsy, thus tumor markers cannot be used to diagnose cancer.

 

Tumor markers can be done in blood, in urine, and in tissue (biopsy). An example of tumor markers in biopsies are estrogen receptor (ER) and progesterone receptor (PR).

 

What are tumor markers good for?

Tumor markers may be good indicators of response to cancer therapy. When cancer patients are undergoing therapy for treatment of their cancer, we usually track tumor markers to see if there is downward trend over the course of therapy indicating that the therapy is working. 

 

Tumor markers are also a good tool to monitor early relapse of certain malignancies. After treatment, tumor markers may be measured to see if the cancer is returning after treatment. Some tumor markers also assist in deciding which treatment is best. For example, the example I mentioned before ER and PR are tumor markers that can be used to pick the best treatment for certain breast tumors.

 

Pitfalls of tumor markers. 

A benign disease can raise some tumor marker levels. Some people without cancer can have high levels of a tumor marker. Tumor marker levels can change over time, and levels may be undetectable until cancer gets worse. 

 

Common tumor markers:

PSA (Prostate specific antigen): Elevated in prostate cancer, BPH, DRE (recently showed to be questionable for screening). PSA is one of the most controversial tumor markers when it comes to screening for prostate cancer. Although PSA has been shown to be elevated prostate cancers, it has also been shown to be increased in BPH, prostatitis, digital rectal exams as well as post ejaculation. This tumor marker remains controversial in screening because there is an uncertainty about the outcome of localizing such prostate cancers. According to the American Urological Association they suggest that patients should be given an abundant amount of education about PSA, and they should ultimately decide if they would like this marker to be used as a tool for screening for their prostate cancer. 

PSA was widely used in the past for prostate cancer screening. It was like the “savior” for men who wanted to avoid digital rectal exam. Well, several years later, PSA increased the number of biopsies and even mortality related to prostate cancer diagnostic tests. The IsoPSA may be a better tool, but it is not ready for prime time yet (listen to episode 60). If you find a PSA higher than 4, refer to urology.

ALP (alkaline phosphatase): Elevated in metastasis to bone and liver and Paget’s disease of the bone. In Paget’s disease, you will not be able to use ALP to tell if the patient has bone cancer or just the progression of the disease, but an incidental elevated ALP can prompt you to investigate and come to a diagnosis of Paget’s disease after an extensive work up. 

ALP is also elevated in many other conditions, for example, obstruction of the biliary tree.

 

AFP (alpha feto-protein): Elevated in hepatocellular carcinoma, yolk sac tumor, neural tube defects, ataxia telangiectasia, mixed germ cell tumors.

 

Beta-hCG (beta human chorionic gonadotropin): Elevated in hydatidiform mole, testicular cancer, mixed germ cell tumors.

After treatment of a molar pregnancy, the patient has regular measurements of hCG until it is undetectable. A rise in hCG may prompt additional treatment or work up because there is an increased risk of choriocarcinoma.

 

CA 19-9 - pancreatic adenocarcinoma.
CA 19-9: When we think of this tumor marker our minds tend to think about the possibility of pancreatic adenocarcinoma. However, this tumor marker is also associated with other malignancies such as biliary tract cancers and esophageal cancer as well. CA 19-9 has less than 1% PPV, but in the case where pancreatic cancer is already diagnosed, screening with CA 19-9 has a positive predictive value of 97%. Also, there is an 80% and 90% sensitivity and specificity respectively for pancreatic cancer, when already diagnosed.

 

CA 125: Elevated in ovarian carcinoma, and malignant ascites. This tumor marker is often associated with epithelial ovarian cancers, often increased when malignancy is present. CA 125 levels are elevated in 85% of women with malignant type ovarian cancer. However, this marker is insensitive to early stages of ovarian cancer and are not very useful. CA 125 has not shown an increase in survival for women with ovarian malignancies.

 

CEA (Carcinoembryonic antigen): Commonly elevated in colon or pancreatic cancers. Less commonly elevated in gastric cancers, breast cancers, medullary thyroid carcinoma, irritable bowel disease, non-small cell lung carcinoma, increased in smokers.[4]

CEA is a tumor marker that is overexpressed in adenocarcinomas especially when it comes to colorectal cancers. When we see elevated CEA values, we tend to think colorectal cancer is imminent however, this is one of the tumor markers that are ultimately one of the most nonspecific. CEA is also elevated in cigarette smoking, PUD, IBD, pancreatitis and medullary thyroid cancers. The American Society of clinical oncology recommends that we monitor CEA levels every two to three months for at least two years with patients for surgical candidates with stage II/III colorectal cancers. 

 

Calcitonin: Elevated in medullary thyroid carcinoma, MEN2A/2B. 
Some doctors may be tempted to measure calcitonin before initiating a GLP-1 receptor agonist medication, these meds are very popular now for diabetes treatment and obesity. Calcitonin measurement is not recommended before starting treatment. Medullary thyroid carcinoma was demonstrated in mice who received GLP-1 RA, not in humans. MEN2 (multiple endocrine neoplasia type 2) and personal and family history of medullary thyroid cancer are contraindications to GLP-1 RA (exenatide, dulaglutide, semaglutide, those meds that end in -tide). 

As a reminder, all MEN2 presents with pheochromocytoma and medullary thyroid carcinoma. MEN2A, additionally presents with parathyroid hyperplasia, and MEN2B presents with mucocutaneous neuromas, GI symptoms and muscular hypotonia (marfanoid habitus). 

 

Chromogranin A: Elevated in neuroendocrine tumors (insulinoma, glucagonoma, VIPoma) carcinoid tumor, small cell lung cancer.

 

LDH (lactate dehydrogenase): Elevation indicates tumor invasiveness. This is widely used test for many non-malignant conditions as well, for example hemolytic anemias.

 

CYFRA 21-2: Elevated in lung cancer (non-small cell type), squamous cell lung carcinoma (68% sensitivity, 94% specificity).[3]

 

SMRP (serum soluble mesothelin related peptide): Elevated in mesothelioma.

 

NSE (neuron specific enolase): Elevated in small cell lung cancer, carcinoid, neuroblastoma, also released 2/2 brain injuries.

 

Monoclonal immunoglobulins: Elevated in multiple myeloma, Waldenstrom macroglobulinemia.

 

S-100: Elevated in malignant melanoma.

 

B2 microglobulin: Elevated in multiple myeloma, CLL.

 

Final remarks.
George: The biggest challenge we face with these biomarkers is the inconsistency of the results which may be influenced by our collection methods and sample storage[4].  The science community has come a long way over the years in assessing these markers and using them to the best of their abilities, however it remains a subject matter that must be further assessed to make sure our research and data does not result in false and misleading outcomes.

Arreaza: For now, use tumor markers with responsibility. Discuss with patients the consequences of elevated tumor markers, as you may end up with more questions than answers. But, we have to be fair and also highlight the role of tumor markers in monitoring response to treatment and cancer recurrence. Also, they may be useful (especially the tissue specific markers in identification of cancers and in the decision on treatments).

 

Conclusion: Now we conclude our episode number 63 “Tumor Markers.” Some of the most common markers were discussed. We hope this information will help you decide when to use tumor makers to evaluate your patients. Remembering which conditions cause elevation for each tumor marker is challenging, but with practice and time, you can master the most common ones. Even without trying, every night you go to bed being a little wiser.

 

Comirnaty®: I want to make sure you know about this. The FDA finally gave official approval to the Pfizer BioNTech COVID-19 vaccine on August 23, 2021. This vaccine now has a brand name: Comirnaty®. It is approved for persons older than 16 years old, however, it continues to be available for children between 12-15 years old. Safety monitoring will continue but so far, this vaccine has a strong evidence of being effective and safe.

Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Harendra Ipalawatte, and George Karaghossian. Audio edition: Suraj Amrutia. See you next week! 

_____________________

References:

New CDC Data: COVID-19 Vaccination Safe for Pregnant People, CDC Online Newsroom, August 11, 2021. https://www.cdc.gov/media/releases/2021/s0811-vaccine-safe-pregnant.html.

 

Talking with Patients Who Are Immunocompromised about an additional dose of an mRNA COVID-19 vaccine, Centers for Disease Control and Prevention, https://www.cdc.gov/vaccines/covid-19/clinical-considerations/immunocompromised-patients.html.

 

Perkins GL, Slater ED, Sanders GK, Prichard JG. Serum tumor markers. Am Fam Physician. 2003 Sep 15;68(6):1075-82. PMID: 14524394. https://www.aafp.org/afp/2003/0915/p1075.html

 

Nagpal M, Singh S, Singh P, Chauhan P, Zaidi MA. Tumor markers: A diagnostic tool. Natl J Maxillofac Surg. 2016;7(1):17-20. doi:10.4103/0975-5950.196135 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242068/

 

Wieskopf Bram, et al, CYFRA 21-1 as a biological marker of non-small cell lung cancer. Chest Journal, Clinical Investigations, vol 108, issue 1, P163-169, July 01, 1995, DOI:https://doi.org/10.1378/chest.108.1.163. https://journal.chestnet.org/article/S0012-3692(16)38611-1/fulltext#relatedArticles.

 

Schrohl, Anne-Sofie, et al. Tumor Markers, from laboratory to clinical utility. Molecular and Cellular Proteomics. Journal of Oncological Studies, vol 2, issue 6, P378-387. June 01, 2003. https://www.mcponline.org/article/S1535-9476(20)34451-0/fulltext.

 

Tumor Markers in Common Use. National Cancer Institute. National Institutes of Health. https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-list.

Further episodes of Rio Bravo qWeek

Further podcasts by Rio Bravo Family Medicine Residency Program

Website of Rio Bravo Family Medicine Residency Program