HE4 in ovarian and uterine cancer

A couple of years we introduced HE4 as a tumour marker for pelvic masses. The idea was to differentiate benign ovarian masses from ovarian cancer in patients without ascites or omental caking. We expected HE4 to be superior to CA125 in premenopausal women. Those young women with localised endometriomas sometimes have scaringly high serum CA125 values. By contrast, we found that postmenopausal women benefited most from HE4. This paper has been published in Gynecologic Oncology last month.

Where do I apply this information for clinical decision-making? Patients with the most benefit are elderly patients who are slightly frail and not the greatest candidates for surgery. These are patients who I really want to avoid surgery if possible at all. The 80+ years women who really don’t want surgery themselves unless absolutely necessary. I review them every 2 months for a little while, checking on their CA125 and HE4. If the markers go up, we may need to bite the bullet. However, we all know that most ovarian masses are benign. To save women from surgery if they don’t need it, is a great value in itself.

In the meantime we also tested HE4 as a serum marker in endometrial cancer. We have first results showing that it is probably very useful to predict the depth of myometrial invasion and the local aggressiveness of the tumour.

Last week I saw a woman with a grade 1 endometrioid adenocarcinoma of the endometrium referred by her general gynaecologist. Her serum CA125 at baseline was 17 U/ml. Her preoperative HE4 was 86 pmol/l –above the normal threshold of 70 pmol/l. Frozen section suggested a deeply invasive tumour and the final report confirms a tumour invading through the entire thickness of the myometrium, thus making it a stage 3A. Obviously, this woman needed an extensive node dissection (which she had) and she will require postoperative treatment as well.

No other marker than HE4 would have pointed to the possibility of more advanced or aggressive disease. In some centres an intraoperative frozen section examination is not even available or it is of such poor quality that it is without value for the patient and the surgeon’s decision making. Blood tests are also a lot cheaper than frozen sections and certainly a lot cheaper than preoperative MRI, which is done regularly at some gynaecological cancer centres within Australia and the UK. I bet that HE4 outperforms MRI by far to determine the depth of myometrial invasion.

There will be limits to all tests and investigations. HE4 is not predictive in high-risk tumour types, such as serous or clear cell carcinomas of the endometrium as well as uterine sarcomas.   

The other issue is that false positive HE4 readings are generated in patients with renal impairment. Sometimes that renal impairment can be mild and the patient might not even know about it because it is clinically irrelevant.

In the future we might also use biomarkers, such as HE4 to determine who will respond to conservative, non-surgical treatment of endometrial cancer. In particular, young women who have not had children as yet and those who are at risk of developing postoperative surgical complications could benefit from that approach. Our group published results on Mirena only recently and we are in the process of preparing an update.  How good would that be to predict who is going to respond and who will not?

The world of cancer surgery is changing fast. Some of those changes are driven by our need to improve survival; by contrast, some of these changes are driven to improve the quality of the survival in cancer types where survival is not the issue. How cool would that be if we could establish a biomolecular profile of a patient recently diagnosed with endometrial cancer and we could predict what treatment option works best. At the moment we can only offer surgery, or surgery, or .... surgery. 

I look forward to the future. 

You can say you read it on the Obermair blog.

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