Transcriptional expression of 8 genes predicts pathological response to first-line docetaxel + trastuzumab-based neoadjuvant chemotherapy

BACKGROUND: Overexpression of HER2 is observed in 20 to 30% of breast carcinomas. The use of trastuzumab has improved the treatment of these patients, especially when it is associated with docetaxel. To optimize the use of this treatment, it seems important to select putative complete responders before treatment administration. METHODS: In this study, we analyzed by quantitative PCR the expression of 28 genes in HER2-overexpressing tumors treated with trastuzumab + docetaxel-based chemotherapy. We then correlated their expression profile with those of trastuzumab-sensitive and resistant cell lines to classify tumors as having a sensitive (pCR) or resistant (non-pCR) profile. Finally, we used public datasets from the GEO website to validate the reduced gene-expression profile obtained. RESULTS: We identified an 8-gene-expression combination that predicted the response to treatment with an accuracy of 76%. Based on public microarray data, we showed that the expression profile was specific to first-line trastuzumab + docetaxel-based treatment with an accuracy of 85%. CONCLUSIONS: Our results showed that by profiling the expression of 8 genes it was possible to predict the response to first-line trastuzumab + docetaxel-based chemotherapy. The use of cancer cell lines as the reference allowed a proper fit with the specificity of different tissues, such as lung or gastric cancers, which could also be eligible to concomitant HER2 inhibition by treatment with trastuzumab or tyrosine kinase inhibitors and docetaxel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1198-9) contains supplementary material, which is available to authorized users

Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195)

Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.

International audiencePrecision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency

An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers

PARP inhibitors yield interesting outcomes for patients with ovarian tumors harboring BRCA1 or BRCA2 mutation, but also with other tumors with homologous repair (HR) deficiency. About 40% of variants are variants of unknown significance (VUS), blocking the use of PARP inhibitors. In this study, we analyzed NGS data from 78 metastatic patients treated with PARP inhibitors. We tested NGS data and in silico predictions to classify VUS as potentially benign or deleterious. Among 41 patients treated with olaparib, three had tumors harboring benign and 26 pathogenic variants, while 12 had VUS. Progression-Free Survival (PFS) analysis showed that benign variants did not respond to olaparib whereas pathogenic variants were associated with a median PFS of 190 days. Surprisingly, median PFS of patients with VUS-carrying tumors suggested that some of them may be sensitive to PARP inhibitors. By testing different in silico predictions and variant allelic frequency, we obtained an algorithm predicting VUS sensitivity to PARP inhibitors for patients with a Performance Status below 3. Our work suggests that VUS in HR genes could be predicted as benign or deleterious, which may increase the number of patients eligible for PARP inhibitor treatment. Further studies in a larger sample are warranted to validate our prediction algorithm.</jats:p

Apoptosis gene signature of Survivin and its splice variant expression in breast carcinoma

Survivin, an anti-apoptotic protein, was described as strongly expressed in human cancers including breast cancer. However, little is known about the association between Survivin variants (Survivin-2B, Survivin-ΔEx3, Survivin-3B, and Survivin-2α) and the other apoptotic-related genes. In this study, we analyzed the apoptosis gene signature of Survivin and its variant expression in breast cancer. Human Apoptosis Gene Arrays were used to screen genes that could be associated with Survivin variants. Expression of the five transcripts was measured by RT-PCR in 135 breast carcinomas and Cox survival analysis was analyzed according to the patient outcome. Significant associations between Survivin transcripts and apoptotic genes were found. Interestingly, Survivin-3B variant showed major inverse correlations with pro-apoptotic genes. In addition, in vitro results indicated that overexpression of Survivin-3B strongly inhibits 5-fluorouracil/epirubicin/cyclophosphamide-induced apoptosis in breast tumor cell lines. In breast carcinomas, uni- and multivariate analysis showed patients with high level of Survivin-3B expression had a shorter overall (P=0.030 and P=0.042 respectively), and disease-free (P=0.024 and P=0.009) survival. Our data suggest that Survivin-3B contributes to cell survival through the anti-apoptotic pathway and that its expression level could be an important factor in determining therapeutic strategies for breast carcinoma.</jats:p

An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers

PARP inhibitors yield interesting outcomes for patients with ovarian tumors harboring BRCA1 or BRCA2 mutation, but also with other tumors with homologous repair (HR) deficiency. About 40% of variants are variants of unknown significance (VUS), blocking the use of PARP inhibitors. In this study, we analyzed NGS data from 78 metastatic patients treated with PARP inhibitors. We tested NGS data and in silico predictions to classify VUS as potentially benign or deleterious. Among 41 patients treated with olaparib, three had tumors harboring benign and 26 pathogenic variants, while 12 had VUS. Progression-Free Survival (PFS) analysis showed that benign variants did not respond to olaparib whereas pathogenic variants were associated with a median PFS of 190 days. Surprisingly, median PFS of patients with VUS-carrying tumors suggested that some of them may be sensitive to PARP inhibitors. By testing different in silico predictions and variant allelic frequency, we obtained an algorithm predicting VUS sensitivity to PARP inhibitors for patients with a Performance Status below 3. Our work suggests that VUS in HR genes could be predicted as benign or deleterious, which may increase the number of patients eligible for PARP inhibitor treatment. Further studies in a larger sample are warranted to validate our prediction algorithm