Ki67 Biomarker in Bladder Cancer May Lead to Improved Outcomes

January 26, 2009 — Measuring the biomarker Ki67 in patients with bladder cancer may help improve outcomes in these patients, say researchers.

A multicenter trial of 713 patients has validated the predictive role of the marker, and now a prospective trial of 300 patients is underway to investigate if therapy based on the biomarker can improve outcomes, said one of the principal investigators, Shahrokh Shariat, MD, PhD, now at the Memorial Sloan–Kettering Cancer Center, in New York City (but until very recently at the University of Texas Southwestern, in Dallas).

Currently, about half of the patients with bladder cancer who undergo a radical cystectomy succumb to the disease, Dr. Shariat explained in an interview with Medscape Oncology. Although survival is improved with the use of perioperative chemotherapy, very few patients currently receive it (about 12%).

Dr. Shariat and colleagues have already shown that Ki67 can identify bladder cancer patients who have a worse prognosis after radical cystectomy, and now they are hoping to show that these patients are the most likely to benefit from chemotherapy.

Ki67 is an established marker of cell proliferation, and has been investigated as a biomarker in several different cancers. However, Ki67 was found not to be useful for predicting chemotherapy benefit in breast cancer, and the American Society of Clinical Oncology Tumor Markers Expert Panel maintains that measurements of the cell cycle should not be used for chemotherapy decision-making, as previously reported by Medscape Oncology.

Ki67 may prove to be useful in bladder cancer because it is very responsive to chemotherapy, Dr. Shariat commented. He explained that a biomarker needs to go through 3 stages of investigation — hypothesis-generating small studies, validation in a multicenter trial, and then a prospective trial investigating whether therapy based on the biomarker can improve outcomes. Ki67 is now at the third stage, and the results of second stage, the multicenter validation, were published January 21 in the Journal of the National Cancer Institute.

Validation of Predictive Role

A predictor role for the biomarker had been suggested by several smaller studies, including 1 carried out by Dr. Shariat and colleagues. That single-center trial of 226 patients treated with radical cystectomy showed that high Ki67 labelling was independently associated with disease recurrence and bladder-cancer-specific mortality after adjustment for tumor stage, grade, and presence of lymphovascular invasion (Clin Cancer Res. 2006;12:7369-7373).

To validate these findings, Dr. Shariat and colleagues conducted this multicenter trial, spanning the United States, Canada, and Europe, involving 713 patients treated with radical cystectomy and bilateral pelvic lymph node removal. They found that Ki67 was a strong predictor of outcome, even after adjustment for age, sex, tumor status, grade, number of positive lymph nodes, and surgical margin status.

Patients with tumors that expressed a high level of Ki67 were 2.4 times more likely to have disease recurrence than those with tumors that expressed low levels of ki67, and were 1.8 times more likely to die from bladder cancer.

The researchers then incorporated Ki67 into a model that includes all known risk factors for predicting disease recurrence, including tumor stage, grade, nodal status, and the presence of lymphovascular invasion.

This model improved the accuracy of predicting which patients would experience disease recurrence (by 2.9% for all patients, and by 4.4% for a subgroup of patients with node-negative disease) and which patients would succumb to disease-specific mortality (by 2.4% for all patients, and by 4.6% for the subgroup).

"In conclusion, routine assessment of Ki67 expression status, along with the assessment of other established predictors of urothelial carcinoma outcome, has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy," the researchers write.

May Increase Use of Perioperative Chemotherapy

Bladder cancer is very sensitive to chemotherapy, and the use of perioperative systemic chemotherapy can reduce the development of systemic disease and improve survival after radical cystectomy, the researchers note. The results are modest but are comparable to those achieved in lung, breast, and colon cancers, they add.

However, only about 12% of patients receive perioperative chemotherapy after radical cystectomy, according to data from the National Cancer Database. Although there are likely to be many reasons for this, one that is "of major importance" is the lack of a way to predict outcomes and, hence, identify the patients most likely to benefit, the authors comment.

This is where they hope that Ki67, along with other factors, will play a useful role.

In the trial that Dr. Shariat and colleagues are currently conducting, they are using Ki67 and 4 other biomarkers to decide what treatment the 300 enrolled patients should receive. The biomarkers will be tested in a biopsy sample taken before cystectomy, and will determine whether the patient will undergo an early cystectomy or receive neoadjuvant chemotherapy and a delayed cystectomy. In addition, the biomarkers will be used to determine whether or not the patient will receive adjuvant chemotherapy after the surgery.

It will take several years to answer these questions, Dr. Shariat said, but he hopes that some results will be available in 2 or 3 years' time.

The researchers have disclosed no relevant financial relationships.

J Natl Cancer Inst. 2009;101:114-119