ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy

Groenendijk, Floris H.; Jong, Jeroen de; Putte, Elisabeth E. Fransen van de; Michaut, Magali; Schlicker, Andreas; Peters, Dennis; Velds, Arno; Nieuwland, Marja; Heuvel, Michel M. van den; Kerkhoven, Ron; Wessels, Lfa; Broeks, Annegien; Rhijn, Bas W.G. van; Bernards, René; Heijden, Michiel S. van der

doi:10.1016/j.eururo.2015.01.014

Cited by 185 publications

(136 citation statements)

References 8 publications

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“…As with any study investigating markers predictive of response to NAC, it is difficult to determine how the rate of pT0 after transurethral resection alone (historically 4.6% at our center) may have affected our results [27]. Other reports examining retrospectively collected samples suggest that alterations in ERCC2 or ERBB2 enhance cisplatin sensitivity, but the heterogeneity of chemotherapy regimens, the number of cycles administered, and exclusion of patients with intermediate responses represent limitations [9,28]. Further confounding cross-study comparison, Groenendijk et al [28] considered pathologically node-positive patients as intermediate or partial responders if the pathologic T stage was ≤T2, excluding this group from the correlation analysis.…”

Section: Discussionmentioning

confidence: 99%

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

Plimack

Dunbrack

Brennan³

et al. 2015

European Urology

413

270

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Background Cisplatin-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. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment 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 analysis The 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 limitations Patients 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. Conclusions: Genomic 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 summary Chemotherapy 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.

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Section: Discussionmentioning

confidence: 99%

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

Plimack

Dunbrack

Brennan³

et al. 2015

European Urology

413

270

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“…It will be interesting to determine their relationships to cigarette smoking [27] and relative sensitivities to NAC [39]. Given that ERCC2 , RB1 [40], and ERBB2 [86] mutations and CNA levels in general [39] have been linked to chemosensitivity, it seems likely that patients with GU tumors will obtain greater direct clinical benefit from NAC than those who have uroA tumors.…”

Section: Discussionmentioning

confidence: 99%

Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset

et al. 2017

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Context Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. Objective The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. Evidence acquisition We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA’s bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. Evidence synthesis The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. Conclusions The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Patient summary Our observation showed that some of subtype-enriched mutations and copy number variations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.

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“…These data suggest that defects in genes that are critical for DNA repair and maintenance of chromatin structure mediate sensitivity to DNA damaging chemotherapy and explain the accumulation of genetic alterations in patients with complete pathologic response to chemotherapy. Another study reported that 9 of 38 complete responders to cisplatin-based neoadjuvant chemotherapy had HER2 missense (mostly activating) mutations, whereas none of 33 non-responders had those (p=0.003) [49]. ERCC2 missense mutations were more common in complete responders, but this association did not reach statistical significance in that study.…”

Section: Novel Candidate Molecular Biomarkers Predictive Of Treatmentmentioning

confidence: 88%

The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches

Grivas

Melas

Papavassiliou

2015

Seminars in Cancer Biology

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ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy

Cited by 185 publications

References 8 publications

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset

The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches

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