Medicosnext
Tumor markers are used for monitoring the effectiveness of treatment. They are used to see if there are recurrent causes of cancer. That is the true use of serum tumor markers, but serum tumor markers have found utility in other segments, as well. For example, there are tumor markers for stratification, tumor markers for screening, and tumor markers that aid you in any cancer diagnosis, such as lung cancer.
Of all healthy women, about 10 percent of them undergo surgery (neoplasm) at some point of time, but only 15-20 percent of them actually have ovarian malignancies for which they undergo surgery.
Ovarian cancer is the fourth most common cancer among women in Nepal, and third leading cause of cancer in India. Globally, it is the sixth most common cancer in women, and it is also the most frequent cause of death (from gynecologic cancer). The incidence rate increases with age and postmenopausal status. They are asymptomatic at early stage, and 75 percent of patients are often diagnosed at the advanced stage.
Prognosis and survival rate
Stage I: 5 years survival for 80-90% patients
Stage III &IV: 5 years survival for 30% patients
Overall: 5 years survival rate is <50%
Basically, when a lady presents with a pelvic mass, she goes to a surgeon or a gynecologist. In a lot of cases, a doctor has to make a decision whether it is a benign or malignant mass. If it is a malignant mass, the patient has to undergo a specialized kind of surgery. Only a few doctors or gynecologists are trained to do the surgery. If it seems like a benign mass, then a surgeon or a gynecologist can do a laparoscopic surgery to remove the tumor. What happens very often is, when a patient undergoes laparoscopic surgery, believing that it is a benign mass, the doctor discovers that it is a malignant tumor and nothing can be done laparoscopically. The patient is then closed and referred to a gynecologist, and the patient is operated again. That means there is somewhere a problem in the identification of risk stratification of that mass, whether it is benign or malignant.
How is that risk stratification currently done?
It is done on the basis of how that mass has developed, family history, trans-vaginal ultrasound, and one tumor marker, CA125, most commonly used for this risk stratification. For ovarian cancer, it has been seen that the survival of a patient is best in the hands of a gynecologist, rather than a surgeon. CA 125 is a good marker for risk stratification, but has certain limitations.
CA125 is elevated in > 90 % of women with advanced disease, and it correlates with tumor volume and stage. In postmenopausal women, CA125 concentrations over 95 U/mL can discriminate between benign verses malignant mass with a PPV of 95%.
But, it has poor sensitivity, as its levels may be high, even in some benign conditions like endometriosis or cysts. Further, CA 125 is high only in about 80 percent of the cancers, not the remaining 20 percent. The sensitivity is especially poor in early stage (1 and 2) cancers, where it is high only in about 50 percent of cancers.
As CA 125 has limitations of poor specificity and sensitivity, especially in the early stages, a number of tumor markers were evaluated, and it has been found that a combination of CA 125 and HE4 actually has the best combination of sensitivity and specificity.
Risk of ovarian malignancy algorithm (ROMA)
In this algorithm, both values of CA 125 and HE4 are put in, and after putting those values, you get to know whether this patient is a low-risk or a high-risk for ovarian malignancy. High-risk patients should be referred, and low-risk patients should be followed up with a gynecologist.
The performance of ROMA is considerably better than either HE4 or CA 125. We can infer from the previous graph that CA 125 levels are high even in conditions like endometriosis, but for benign conditions, the levels of HE4 are not high. So, HE4 gives more specificity to the combination.
ROMA has 10 percent higher specificity compared to CA 125 with 78 percent specificity. The specificity increases to 91 percent with ROMA. Also, if you see for sensitivity, compared to 86 percent for CA 125, the sensitivity is 93 percent for ROMA. So, there is almost a 10 percent difference in sensitivity if you use ROMA.
In stage 1 and stage 2 cancers, many of these patients have low values of CA 125. But regarding HE4, even in stage 1 and stage 2 cancers, the levels are high. This reveals that even in early stage cancers, if you use ROMA, you see improvement in sensitivity. The sensitivity goes up by 10 percent.
Overall, I think adding HE4 to CA 125 will raise the level of specificity, sensitivity, and sensitivity also for detecting the early stages of ovarian cancer. What happens is, instead of the patient being referred by a gynecologist or general surgeon after surgery to a gynecologist, the patient can be referred at the time of the diagnostic workup.
This is about the risk stratification of pelvic mass. This is not the screening marker. ROMA is not a screening algorithm. The starting point is a patient with a pelvic mass, and ROMA can be used there.
When the patient has been detected with ovarian cancer and is being treated, again, CA 125 and HE4 can be used. During the treatment, the first of the two markers may be changed, and even for monitoring of the patient, both CA 125 and HE4 should be used together. Compared to all the others, if you add HE4 to CA 125, it gives the best combination of sensitivity and specificity for stratification.
Risk factors for ovarian cancer
Age
4.7 per 100,000 in <50 years of age to 29.6 per 100,000 in 50-64 years
70% cases occurs after 50 years
Family h/o ovarian or breast cancer (3-5 % lifetime risk)
Inherited mutations:
Hereditary breast and ovarian cancer (HBOC) syndrome (BRCA 1 or 2 mutation)—45% lifetime risk
Hereditary nonpolyposis colorectal cancer (Lynch syndrome)—12% lifetime risk
Other associated risk factors
Low parity
Primary infertility
Endometriosis
Early menarchal age
Late menopausal age
Living in Western industrialized country
High BMI (especially in premenopausal)
Unmet needs in ovarian cancer diagnostics
Prevention
Screening
Early detection
Differential diagnosis between benign and malignant pelvic masses
Monitoring in women who don’t have elevated CA125
