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Researchers Aim to Validate ERCC2 as Therapy-Response Biomarker in Bladder Cancer


NEW YORK – Researchers from Massachusetts General Hospital have begun new retrospective and prospective clinical studies to validate results published last month in Clinical Cancer Research showing mutations in the DNA repair gene ERCC2 are associated with sensitivity and long-term response to chemoradiation in patients with muscle-invasive bladder cancer (MIBC).

David Miyamoto, a radiation oncologist at Massachusetts General Hospital and co-corresponding author on the study, said the work was part of his group's ongoing research to discover and develop biomarkers to guide personalized therapy for patients with bladder and prostate cancer.

The standard treatment for MIBC is cisplatin-based chemotherapy followed by radical cystectomy, or surgical removal of the bladder. Although this treatment gives the patient the best chance for a cure, the surgery has high rates of morbidity and a negative impact on quality of life.

An alternative developed more recently is a bladder-preserving approach called trimodality therapy which pairs transurethral tumor resection with chemotherapy and radiation. In a pooled analysis of long-term outcomes in MIBC patients who received trimodality therapy, the complete response rate was 69 percent with five- and 10-year overall survival rates of 57 percent and 36 percent, respectively, and disease-free survival rates of 71 percent at five years and 65 percent at 10 years.

Miyamoto said trimodality therapy is "equivalent to [radical cystectomy] in long-term outcomes in well-selected patients," with the key being selection of patients most likely to benefit. "Right now, we're lacking in tools to identify those appropriate patients."

Currently, patients are selected for trimodality therapy based on clinical and pathological features, such as the size and location of the tumor. "Over time, through our experience treating such patients and also patients with much more extensive tumors, we've seen a lot of variability in treatment responses," Miyamoto said. "That points to something intrinsic in the biology of the tumors that makes some tumors more sensitive to chemoradiation than other tumors, and not just basic characteristics like the size or location of the tumor."

That insight plus evidence from other cancers linking certain genomic alterations to increased sensitivity to chemotherapy and radiation led Miyamoto and his colleagues to search for biomarkers to identify patients who would be good candidates for bladder-sparing trimodality therapy.

In the study, Miyamoto's group conducted a retrospective analysis of tumor samples from MIBC patients at Massachusetts General Hospital using whole-exome sequencing to determine bladder-intact event-free survival and correlated that with genetic alterations. For most tumors, Miyamoto said his team was also able to perform whole-transcriptome profiling to characterize the RNA expression profile of the tumor.

The biggest challenge in the study, according to Miyamoto, was extracting a sufficient quantity and quality of DNA and RNA to carry out the sequencing and transcriptomic profiling, given that the tumors had been collected from as early as 1986 through 2015. "Many of the tumors failed to yield [a] sufficient quantity of nucleic acids for processing, so we had significant dropout in terms of usable sample because of that," Miyamoto said.

The final study cohort included 76 patients who had a median age of about 72 years. The study showed that roughly half of the patients had a favorable long-term response to trimodality therapy, and half had an unfavorable long-term response, meaning they required a radical cystectomy as a salvage therapy.

As the researchers looked closer at the data for clues as to why one group fared so much better than the other, they first considered tumor mutational burden, based on evidence in the scientific literature linking it to immunotherapy and some chemotherapy response. However, they did not find an association of tumor mutational burden with outcomes in the study group.

The next avenue they explored was a possible link between trimodality therapy outcomes and alterations in DNA damage response genes. Miyamoto said they thought those genes might be involved because radiation kills cancer cells by damaging their DNA, and if cancer cells have defects in the ability to repair DNA, they are believed to be more susceptible to radiation treatment. That link had never been confirmed with radiation therapy for bladder cancer, however.

This line of investigation proved fruitful, and it turned out that DNA repair mutations, particularly ERCC2, were highly significantly associated with better outcomes, both in terms of bladder-intact event-free survival and local regional control of the cancer.

ERCC2 is a DNA helicase that is involved in excision repair in the cell. It has previously been found to be associated with better outcomes after neoadjuvant cisplatin therapy in bladder cancer in the absence of radiation or other treatments.

Miyamoto's group went on to explore the link between ERCC2 mutations and response to chemoradiation therapy in bladder cancer using in vitro studies and found that the presence of ERCC2 also confers sensitivity to chemoradiation in bladder cancer cells.

"The ERCC2 mutation is … a potentially very powerful biomarker that could be used to identify patients who would be sensitive to chemoradiation therapy for muscle-invasive bladder cancer and would be predicted to have a long-term sustainable response to treatment," Miyamoto said.

Miyamoto and collaborators Jason Efstathiou, a radiation oncologist at Massachusetts General, and Kent Mouw, a radiation oncologist at Dana-Farber Cancer Institute, have now moved on to validation studies, which they are carrying out retrospectively and prospectively. In retrospective studies, they are sequencing tumors from multi-institutional cohorts of bladder cancer patients who have been treated with chemotherapy and radiation in six trials conducted by NRG Oncology to see if ERCC2 and other potential gene mutations can be validated as biomarkers of long-term response.

Additionally, Miyamoto's team will attempt to validate ERCC2 as a biomarker of response prospectively in the SWOG-NRG 1806 trial, in which researchers are studying chemoradiation therapy with or without Genentech's Tecentriq (atezolizumab) in MIBC patients following tumor resection. That trial is nearing completion of accrual, Miyamoto said, and the investigators will incorporate ERCC2 as well as several other candidate biomarkers into correlative studies. "The idea is to validate this biomarker as something that could potentially be used in clinical practice to identify patients who would be eligible for [bladder-preserving trimodality therapy]," Miyamoto said.

Miyamoto said funding and support for this line of research and potential commercialization of a biomarker test for ERCC2 is a challenge because the test is linked to a generic chemotherapy and radiation regimen, and therefore unlikely to attract partnership or support from the pharmaceutical industry. Instead, funding for these studies thus far has been through the National Institutes of Health and philanthropic funds. Miyamoto said that multidisciplinary collaboration with radiation oncologists, medical oncologists, pathologists and urologists has also been critical in carrying out the work.

The researchers have discussed the possibility of commercializing an ERCC2 test to guide MIBC treatment, but have made no definite plans, Miyamoto said. Tests for the gene are already available through commercially available gene panels, he said, so it could be as simple as making sure the result for ERCC2 is made available to bladder cancer patients during routine genomic testing of the tumor. If the significance of ERCC2 is confirmed through validation studies, he added, patients could receive the test at the time of diagnosis, before treatment decisions have been made, with the results used to guide the patient toward the most appropriate therapy.