Dataset Information

Defects in DNA Repair Genes Confer Improved Long-term Survival after Cisplatin-based Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

ABSTRACT: Cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in muscle-invasive bladder cancer (MIBC). However, only a subset of patients (25-50%) have a pathologic complete response at cystectomy. Using a cohort of 58 patients from two phase 2 trials, our group previously reported that mutations in the ATM, RB1, and FANCC genes correlate with complete response to cisplatin-based NAC, and consequently improve OS and disease-specific survival (DSS). These trials enrolled patients with T2-4 (N0 or N1) MIBC and treated them with accelerated/dose-dense NAC with methotrexate, vinblastine, adriamycin, and cisplatin, or gemcitabine and cisplatin, with a plan for curative cystectomy. Updated long-term follow-up (median 74 mo) shows that significantly greater OS and DSS was maintained for patients with ATM, RB1, or FANCC mutations. The 5-yr survival rate for patients with at least one mutation was 85%, compared to 45% for patients without a mutation. On the basis of the associations with response and long-term OS and DSS, we propose that these alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients who are most likely to benefit from NAC before radical cystectomy. PATIENT SUMMARY: In this report we looked at outcomes for patients with muscle-invasive bladder cancer treated with cisplatin-based chemotherapy before surgery (neoadjuvant) who had mutations in a set of DNA damage repair genes (ATM, RB1, FANCC) compared to those who did not. We found that patients who had at least one mutation in one of these genes survived longer after receiving cisplatin chemotherapy before surgery than patients who did not.

SUBMITTER: Miron B

PROVIDER: S-EPMC7689684 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking.ObjectiveTo discover and validate biomarkers predictive of response to NAC for MIBC.Design, setting, and participantsPretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory.Outcome measurements and statistical analysisThe mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set.Results and limitationsPatients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets.ConclusionsGenomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin.Patient summaryChemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Project description:BackgroundBladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown.Patients and methodsWe identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias.ResultsWe identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation.ConclusionThese results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.

Project description:BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC).ObjectiveTo determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC.Design, setting, and participantsClinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC.Outcome measurements and statistical analysisPathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method.Results and limitationsPatients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio=0.4 [95% confidence interval=0.18-0.84] p=0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p=0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p=0.04) and the validation (15.7% [12/70] vs 0% [0/24], p=0.03) cohort.ConclusionsPatients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered.Patient summaryA retrospective cohort study of patients with "primary" and "secondary" muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy.

Dataset Information

Defects in DNA Repair Genes Confer Improved Long-term Survival after Cisplatin-based Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets