ORLANDO – Gene expression profiling can identify intrinsic bladder cancer subtypes, predict the clinical response to neoadjuvant chemotherapy, and serve as a decision aid for selecting treatments for individual patients, evidence from a phase II trial suggests.
Among 60 bladder cancer patients scheduled for treatment with conventional neoadjuvant therapy plus bevacizumab(Avastin), a prognostic gene expression profile performed prior to chemotherapy accurately classified tumors into a basal subtype that is chemosensitive, a p53-like subtype that is chemoresistant and prone to bone metastasis, and a luminal subtype that retains some chemosensitivity and may respond to therapy with a fibroblast growth factor inhibitor, reported Dr. Arlene O. Siefker-Radtke of the University of Texas MD Anderson Cancer Center, Houston.
Dr. Arlene Siefker-Radtke
“The time has come for us to no longer think of bladder cancer as one single disease. Application of these biomarkers will fundamentally change how we treat bladder cancer,” she said at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.
Her group had previously found evidence to suggest that bladder cancer can be divided into the following three intrinsic subtypes:
• Basal, the most highly proliferative type with historically, the worst clinical outcomes.
• Luminal, with intermediate markers of proliferation and enrichment for the fibroblast growth factor receptor 3.
• P53-like, with the lowest levels of proliferation and highest expression of stromal markers.
In the current study, the investigators performed gene-expression profiling on tissues from transurethral resections (from 38 patients) and cystectomy specimens (from 23 patients ) from patients enrolled in a phase II trial of neoadjuvant chemotherapy with dose-dense methotrexate, vincristine, doxorubicin and cisplatin (ddMVAC). They also performed profiling on a validation sample from 49 patients treated with perioperative MVAC in a previous clinical trial.
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In an analysis of overall survival among patients who had undergone transurethral resection they found that 5-year OS was 91% for the 11 patients with the basal tumor subtype, 73% for 11 patients with the luminal subtype, and 36% for those with the p53-like subtype (P = .015).
Neoadjuvant chemotherapy altered the natural course of the basal subtype, Dr. Siefker-Radtke said, noting that among chemonaive patients with this subtype in previous studies, the 5-year OS was just 30%.
The investigators hypothesized that the highly proliferative basal subtype would more susceptible to DNA-damaging agents, a supposition supported by evidence from tumor downstaging studies, They found that 45% of basal tumors were downstaged to pT0N0, compared with 36% of luminal tumors, and 25% of p53-like tumors. The differences were not statistically significant, however, because of the small sample size.
They also found that bone metastases were associated exclusively with the p53-like subtype, with 56% of patients with this tumor type developing bone metastases within 2 years of their initial diagnosis.
To validate their findings, the authors applied gene expression profiling to samples from 49 patients enrolled treated with MVAC in 2001. Here, too, they found that the basal subtype was associated with better survival, with a 5-year OS of 77%, compared with 56% each for the luminal and p53-like subtypes (P = .021).
“We found that a prognostic gene-expression profile that had been previously reported in chemonaive patients was now predictive for clinical outcomes in the setting of neoadjuvant-based chemotherapy with dose-dense MVAC. Use of gene expression profiling in determining subtype may help select the appropriate group of patients for neoadjuvant chemotherapy. I think this also shows the impact of aggressive chemotherapy on a highly proliferative basal subtype,” Dr. Siefker-Radtke said.
“The p53-like group was associated with chemoresistance and bone metastases, and I think that this subtype might select for patients who would benefit from agents inhibiting stromal interactions, and also reflect a group of patients who might benefit from initial surgery,” she added.