BRCA1 mRNA expression in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 31, 2008

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Presenter: A. Font
Presenter's Affiliation: ICO Hospital Germans Trias i Pujol, Badalona, Spain; Univerdidad Complutense, Madrid, Spain
Type of Session: Scientific

Background

  • In the form of meta-analysis, an overall survival benefit has been demonstrated with the use of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy in patients with locally advanced bladder cancer, as compared to radical cystectomy alone (Lancet, 2003).
  • Although the majority of patients with reasonable performance status who are planned to undergo radical cystectomy receive cisplatin-based chemotherapy, no tumor or clinical marker currently exists to predict response to treatment.
  • Platinum-based chemotherapy is associated with toxicities such as myelosuppression, renal toxicity, and sensorineural hearing loss that may significantly affect both patient safety and health-related quality of life. While this treatment is still commonly given to patients, avoidance of platinum-based chemotherapy in patients with a decreased likelihood of sensitivity to these agents could certainly be beneficial.
  • Mutations in the BRCA1 gene (breast cancer susceptibility gene 1) have been associated with both increased risk of development of certain cancers, and resistance to chemotherapy.
    • BRCA1 mutations are associated with a familial syndrome that confers increased risk of developing breast, prostate, and ovarian cancers.
    • Overexpression of BRCA1 mRNA has recently been demonstrated to be predictive of in vitro chemosensitivity to cisplatin and docetaxel in metastatic lung and gastric cancers (Wang, 2008).
    • Similar findings have been documented in ovarian cancer patients (Quinn, 2007). 
  • This study was undertaken to evaluate the role of overexpression of BRCA1 mRNA in bladder cancer patients with regard to response to treatment, disease-free survival, and overall survival.

Materials and Methods

  • A cohort of 98 patients with muscle-invasive bladder cancer treated with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy was considered in this study. Tissue from tumor biopsy was available for pathologic review in 57 cases.
  • Median patient age was 64 years, and 94% of patients were of male sex. Tumors were locally-advanced (T3 – T4, N0, M0) in 82% of cases; 8 patients had involvement of regional lymph nodes, and 2 patients had involvement of distant lymph nodes.
    • Chemotherapy consisted of cisplatin, methotrexate, and vinblastine in 35 cases, and cisplatin with gemcitabine in 22 cases.
    • A median of three cycles of chemotherapy were given prior to radical cystectomy.
  • Biopsy tissue from these 57 patients was embedded in paraffin and RNA was extracted. Real-time PCR was performed on tissue samples to determine the degree of expression of BRCA1 mRNA. 
  • BRCA1 mRNA level was classified as low, intermediate, or high in each case.
  • Pathologic response at time of cystectomy, as well as disease-free and overall survival were considered with regard to BRCA1 mRNA levels.

 

Results

  • Based on tumor biopsy tissue, BRCA1 mRNA levels were found to be low in 35% of patients, intermediate in 32%, and high in 32%.
    • Factors including patient age, histology, lymphatic invasion, and cancer stage were considered, and did not correlate significantly with BRCA1 mRNA expression levels.
  • Overall, complete pathologic response to chemotherapy was seen in 50% of patients.
    • Excellent pathologic response was seen in 66% of patients with low or intermediate BRCA1 mRNA expression, and in 23% of patients with high levels of expression (p = 0.01).
  • With a minimum follow-up of three years, median disease-free survival (DFS) in the overall group was 49 months, and was highly correlated with BRCA1 level; DFS was120 months in patients with low BRCA1 mRNA levels, 184 months in those with intermediate levels, and 14 months in those with high levels (p = 0.03).
  • Five-year overall survival was 63% in patients with low or intermediate BRCA1 mRNA expression, and 23% in those with high levels (p = 0.009).
  • On multivariate analysis for DFS, only BRCA1 mRNA levels and lymphatic invasion were found to be prognostic factors:
    • Intermediate expression levels were associated with a hazard ratio of 1.16 with regard to DFS (95% CI 0.4 – 3.36, p = 0.77); and high expression levels with a hazard ratio of 3.1 (95% CI 1.15 – 8.40, p = 0.02).
    • Lymphatic invasion was associated with a hazard ratio of 7.8 with regard to DFS (95% CI 2.54 – 23.9, p < 0.0001).
 

Author's Conclusions

  • The authors conclude that low levels of expression of BRCA1 mRNA correlate significantly with improved pathologic response to neoadjuvant cisplatin-based chemotherapy, as well as improved DFS and overall survival following radical cystectomy for muscle-invasive bladder cancer. They note that patients with low levels of expression should receive a cisplatin-based regimen.
  • They note that use of taxane-based chemotherapy could be considered in patients with high levels of BRCA1 mRNA expression to potentially increase tailoring of treatment to genetic characteristics.

Clinical/Scientific Implications

  • This study was carried out in order to assess the role of BRCA1 overexpression, a known factor in decreased platinum-based chemotherapy sensitivity in several cancers, in the treatment response of patients with muscle-invasive bladder cancer.
  • BRCA1 is a gene involved in multiple DNA damage repair pathways and pathways involved in cellular responses to microtubule damage, and has now been demonstrated by several groups to affect sensitivity to platinum chemotherapy agents.
  • The data presented here suggests that BRCA1 overexpression also plays a role in response to cisplatin-based chemotherapy in bladder cancer.
  • In the setting of bladder cancer as well as several other cancers, the question remains as to whether BRCA1 overexpression is a prognostic factor, or only a predictive factor for response to treatment.
  • In this study, BRCA1 expression levels did not correlate significantly with tumor histology or stage, or with lymphatic invasion. In fact, patient and tumor characteristics were similar across the three groups with varied BRCA1 expression levels. This suggests that bladder cancer tumor characteristics may not be affected by BRCA1 levels, but rather that these levels may affect response to cisplatin, thereby affecting prognosis indirectly.
  • Assessment of BRCA1 levels and correlation of outcome in patients not receiving chemotherapy would be interesting in light of this.
  • Although the authors’ conclusion that patients with low BRCA1 mRNA levels should continue to receive cisplatin-based chemotherapy seems reasonable based on the data presented, extrapolation to conclude that patients with high BRCA1 levels should not is not completely supported by this nor other data, nor is the conclusion that taxanes should be considered in treatment of these patients.
  • Rather, a randomized controlled trial could potentially be indicated comparing response to cisplatin-based chemotherapy to other, possibly taxane-based, regimens in patients with high BRCA1 expression levels.
  • Still, this study is an important addition to the body of literature regarding DNA repair genes and sensitivity to chemotherapy. As more knowledge is gained in this field, more trials comparing sensitivity to various drugs and treatment regimes will be indicated. Certainly, this process will ultimately contribute to further customization of treatment regimens for patients with bladder and other cancers.

Patient Summary


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