TP53 Signature Research Articles

TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies.Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed.The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876–16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2− subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group.The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

TP53 Signature Score Predicts Prognosis and Immune Response in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered a heterogeneous disease and achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered a surrogate biomarker of a favorable prognosis. Previously, the TP53 signature (TP53sig)-score, the expression profile of 33 genes, has been reported to predict the prognosis of all types of early-stage breast cancer. Herein, we analyzed whether the TP53sig-score can be used to subclassify a TNBC cohort and investigated the molecular biological characteristics of the higher TP53sig-score. Publicly available data from TCGA (RNA-sequence) and METABRIC (microarray) and expression data from real clinical specimens (NanoString Technologies) were used to explore the prognosis and molecular features of TNBC. The high TP53sig-score group in the present study and the cohort in METABRIC tended to have a worse prognosis than the low TP53sig-score group (p=0.583 and 0.196, respectively). In both the pCR and non-pCR groups, the high TP53sig-score patients tended to have a poor prognosis (p=0.0739). Moreover, when the NAC response and TP53sig-score were combined, the five-year breast cancer-free rate among the four groups differed significantly (p=0.043). In addition, high TP53sig-score was related to gene ontology terms, such as "cell differentiation" and "innate immune response". Notably, this group had the potential to respond favorably to immunotherapy according to the tumor immune dysfunction and exclusion model. The combination of the response to NAC and the TP53sig-score in TNBC was able to predict an unfavorable prognosis. Furthermore, patients with a high TP53sig-score showed a favorable response to immunotherapy.

TP53 Signature Can Predict Pathological Response From Neoadjuvant Chemotherapy and Is a Prognostic Factor in Patients With Residual Disease.

The TP53 signature that predicts the mutation status of TP53 has been shown to be a prognostic factor and predictor of neoadjuvant chemotherapy (NAC) response. The current study sought to investigate the utility of the TP53 signature for predicting pathological complete response (pCR) and its prognostic significance among patients with residual disease (RD). The study followed a retrospective cohort study design. Patients with T1-3/N0-1 from a cohort of those with HER2-negative breast cancer who received NAC were selected. Ability to predict pCR was evaluated using odds ratio, positive and negative predictive values, sensitivity, and specificity. Prognostic factors in the RD group were explored using the Cox proportional hazards model with distant recurrence-free survival (DRFS). Four independent cohorts were used for validation. A total of 333 eligible patients were classified into the TP53 mutant signature (n = 154) and wild-type signature (n = 179). Among the molecular and pathological factors, the TP53 signature had the highest predictive power for pCR. In 4 independent cohorts (n = 151, 85, 104, and 67, respectively), pCR rate in TP53 mutant signature group was significantly higher than that in the wild-type group. Univariate and multivariate analyses on DRFS in the RD group identified the TP53 signature and nodal status as independent prognostic factors, with the former having a better hazard ratio than the latter. After comparing DRFS between 3 groups (pCR, RD/TP53 wild-type signature, and RD/TP53 mutant signature groups), the RD/TP53 mutant signature group showed significantly worse prognosis compared with others. The RD/TP53 wild-type signature group did not exhibit inferior DRFS compared with the pCR group. Our results showed that the TP53 mutant signature can predict pCR and that combining pathological response and TP53 mutant signature allows for the identification of subgroups with truly poor prognosis.

TP53 signature diagnostic system using multiplex reverse transcription\u2013polymerase chain reaction system enables prediction of prognosis of breast cancer patients

BackgroundTP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status.MethodsWe developed a multiplex reverse transcription–polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed.ResultsThe diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer.ConclusionThis simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer.

Development and Validation of a Novel TP53 Mutation Signature That Predicts Risk of Metastasis in Primary Prostate Cancer.

Prostate tumors with TP53 gene mutations are molecularly heterogenous, and the presence of TP53 gene mutations has been linked to inferior outcomes. We developed an RNA-based gene signature that detects underlying TP53 gene mutations and identifies wild-type prostate tumors that are analogous to TP53-mutant tumors. Using genomic expression profiles from The Cancer Genome Atlas, we developed a mutation signature score to predict prostatic tumors with a molecular fingerprint similar to tumors with TP53 mutations. Area under the receiver operating characteristic curve assessed model accuracy in predicting TP53 mutations, and Cox regression models measured association between the signature and progression-free survival and metastasis-free survival (MFS). The TP53 signature score achieved an area under the receiver operating characteristic curve of 0.84 in the training and 0.82 in the validation cohorts for predicting an underlying mutation. In three retrospective cohorts, a high score was prognostic for poor 5-year MFS: 46% versus 81% (hazard ratio [HR], 3.05; P< .0001; Johns Hopkins University cohort), 64% versus 83% (HR, 2.77; P< .0001; Mayo Clinic cohort), and 71% versus 97% (HR, 6.8; P= .0001; Brigham and Women's Hospital cohort). The signature also identified TP53 wild-type tumors molecularly analogous to TP53 mutant tumors, wherein high signature score correlated with worse 5-year MFS (50% vs. 82%; HR, 3.05; P< .0001). This novel mutational signature predicted tumors with TP53 mutations, identified TP53 wild-type tumors analogous to mutant tumors, and was independently associated with poor MFS. This signature can therefore be used to strengthen existing clinical risk-stratification tools.

Reassessing the role of high dose cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia.

A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18–77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17–0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16–0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

Evaluation of DNA repair biology signatures to predict specific carboplatin (C) versus docetaxel (D) benefit in advanced triple-negative breast cancer (aTNBC).

1074 Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 &amp; DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT &amp; recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 &amp; 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT &amp; REC. CIN70 increased from PT to REC, DDRD (non-significantly) &amp; PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 &amp; DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]

Development of diagnostic kit for in vitro diagnostics of the TP53 signature in early breast cancer

Abstract Background Diagnostic tests based on gene expression signatures identified by transcriptome analyses have been developed and these have been used for predicting prognosis, recurrence and/or effect of anticancer drugs including endocrine therapies in clinical practice of breast cancer, ahead of other cancer types. We have previously reported that TP53 signature, which has the ability to determine TP53 mutation status, are an independent prognostic factor of breast cancer, and also shown that the TP53 signature has better predictability of prognosis and efficacy on chemotherapies than the TP53 mutation status and other known clinic-pathological factors. Objects The aim of this study is to develop the diagnostic kit for in vitro diagnostics based on the TP53 signature. Methods We adopted an nCounter system (NanoString) because it has robust ability to analyze a gene expression signature of the TP53 signature from a small amount of RNA derived from archival FFPE tissues. Results We have designed a specific probe set for IVD of the TP53 signature and programed a new algorithm to determine the status of TP53 signature from the identified expression data. The algorithm has the characteristic that is hard to be affected by the outliers than previous algorithm (the algorithm cannot be disclosed). Using this method, we determined status of TP53 signature of 220 stage I-II breast cancers. The predictability of recurrence by the IVD of the TP53 signature will be shown in this study. We are also conducting a retrospective-prospective analysis of over 500 breast cancers as the validation study of the IVD under cooperation of JBCRG, OOTR. From this study, the predictability of the pathological CR (pCR) after neoadjuvant chemotherapies and the prognosis by the IVD will be also shown. Conclusion The TP53 signature diagnostic kit is expected to be a clinically useful biomarker for prediction of prognosis, recurrence and efficacy of perioperative chemotherapy in breast cancer.

Elevation of the TP53 isoform Δ133p53β in glioblastomas: an alternative to mutant p53 in promoting tumor development.

As tumor protein 53 (p53) isoforms have tumor‐promoting, migration, and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full‐length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT‐qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumor‐associated macrophage content, and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163‐positive macrophages and wild‐type TP53. In situ‐based analyses found Δ133p53β expression localised to malignant cells in areas with increased hypoxia, and in cells with the monocyte chemoattractant protein C‐C motif chemokine ligand 2 (CCL2) expressed. Tumors with increased Δ133p53β had increased numbers of cells positive for macrophage colony‐stimulating factor 1 receptor (CSF1R) and programmed death ligand 1 (PDL1). In addition, cells expressing a murine ‘mimic’ of Δ133p53 (Δ122p53) were resistant to temozolomide treatment and oxidative stress. Our findings suggest that elevated Δ133p53β is an alternative pathway to TP53 mutation in glioblastoma that aids tumor progression by promoting an immunosuppressive and chemoresistant environment. Adding Δ133p53β to a TP53 signature along with TP53 mutation status will better predict treatment resistance in glioblastoma. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008–2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

STAT3/PIAS3 Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube.

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739-50. ©2018 AACR.

Molecular and clinical features of the TP53 signature gene expression profile in early-stage breast cancer.

PurposeTP53 signature has a robust predictive performance for prognosis in early-stage breast cancer, but the experiment that reported this relied on public microarray data and fresh-frozen samples. Before TP53 signature can be used in a clinical setting, a simple and low-cost diagnostic system using formalin-fixed paraffin-embedded (FFPE) samples is needed. New treatments based on the biological characteristics of TP53 signature are expected to follow.Experimental DesignTP53 signature was evaluated in 174 FFPE early breast cancer specimens using digital quantification via the nCounter technique (NanoString). Patients were classified as TP53 signature mutant type (n = 64) or wild type (n = 110). Predictive power of TP53 signature was compared with those of other gene expression signatures in 153 fresh-frozen samples of the same cohort by RNA-seq. The molecular features of TP53 signature were elucidated using TCGA omics data and RNA-seq data to explore new therapeutic strategies for patients with TP53 signature mutant type.ResultsTP53 signature was a strong predictor of prognosis and was also more accurate than other gene expression signatures and independent of other clinicopathological factors. TCGA data analysis showed that risk score of TP53 signature was an index of chromosomal and genomic instability and that TP53 signature mutant type was associated with higher PD-L1 expression, variation in copy numbers, and numbers of somatic mutations.ConclusionsTP53 signature as diagnosed using the nCounter system is not only a robust predictor of prognosis but also a potential predictor of responsiveness to immune checkpoint inhibitors.

90P - Molecular feature and clinical use development of gene expression profile “TP53 signature” in early stage breast cancer

90P - Molecular feature and clinical use development of gene expression profile “TP53 signature” in early stage breast cancer

1693P - Development of TP53 signature diagnostic system using multiplex RT-PCR and observational study to confirm the prognostic value of TP53 signature in breast cancer

1693P - Development of TP53 signature diagnostic system using multiplex RT-PCR and observational study to confirm the prognostic value of TP53 signature in breast cancer

Abstract LB-130: STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube

Abstract Objectives: Our recent studies in human samples have demonstrated constitutive activation of STAT3 Tyr705 and loss of protein inhibitor of activated STAT3 (PIAS3) in STICs in the fallopian tubes and advanced HGSC tissues. The goal of this current study is to identify and elucidate the molecular mechanisms leading to the initiation and development of HGSC through STAT3 activation and low levels or absence of PIAS3 in the fallopian tube (FT). Methods: Human tissues–benign normal FTs, STICs (without ovarian cancer) and HGSC—were evaluated for expression of STAT3/PIAS3 (as compared with their known TP53 signature) and their target proliferation genes. Isolated primary fallopian tubal serous epithelial carcinoma (FTSEC) cells from FT and immortalized FT cells were also utilized and were evaluated with real time PCR, IHC, ICC, western blots, cloning and orthotopic mouse models. Results: We observed high-level expression of pSTAT3 Tyr705, and decreased levels of PIAS3, in dysplastic areas of FT obtained from patients with and without cancer and advanced stage HGSC (as compared to high PIAS3 low pSTAT3 expression in normal benign FT). In addition, FT cells transfected with a STAT3 overexpression construct showed translocation of pSTAT3 and c-Myc into the nucleus. Further, the in vivo experiments demonstrated that the overexpression of STAT3 in FTSECs promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. In contrast, STAT3 knockdown in ovarian cancer cells was associated with reduced tumor growth and metastasis in vivo. Conclusions: The STAT3 pathway may play a critical role in the development of STIC lesions and their progression to HGSC. We will further screen more FT samples and number of human tissues from various stages of HGSC along with an in vivo mouse model of HGSC in order to establish the oncogenic role of STAT3 and expression levels of PIAS3 in ovarian HGSC. Our current and future findings offer an opportunity to address the clinically important questions that are critical for cancer prevention and early detection in deadly HGSC. Citation Format: Uksha Saini, John Wallbillich, Maria Riley Riley, John M. Fowler, Ross Wanner, Jenny Lester, Beth Karlan, Paul Goodfellow, Adrian Suarez, David Cohn, Karuppaiyah Selvendiran. STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-130.

P1-1-25 - TP53 mutation signature can predict prognosis of early lung adenocarcinoma

Background: In lung cancer, structurally mutation of TP53 is frequently observed, but prognosis of the patients with TP53 mutation is controversial. We have reported that expression profile of 33 genes, which predicts TP53 mutation status (TP53 signature), has the ability to predict overall survival and recurrence after surgery in breast cancer (Cancer Sci. 99:324-34,2008) and also the efficacy of NAC and recurrence after surgery in breast cancer (O1-15-2, JSMO 2014). The aim of this study is to determine whether the TP53 signature can also predict overall survival of early lung adenocarcinoma. Materials and Method: A public microarray data set containing stage 1-2 lung adenocarcinomas of 246 Japanese patients (Cancer Res.72:100-11, 2012), is obtained from Oncomine. Of 246 patients, we used 133 patients' data, which follow up time is over 5 years. We divided the patients into two groups according to EGFR mutation status (57 wild and 76 mutant type). Each groups was classified using TP53 signature by clustering method. Result: Sixty five percent (37 of 57) of EGFR wild patients and 46% (35 of 76) of EGFR mutant patients is determined as mutant type of TP53 signature. There is no statistically significant difference in clinical stage between mutant type and wild type of TP53 signature. Almost all TP53 mutant signature patients of EGFR wild type have smoking history. Regardless of EGFR mutation status, patients in mutant type of TP53 signature groups showed significantly worse overall survival than patients in wild type TP53 signature groups (p < 0.05). In 41 patients with EGFR mutation and TP53 wild signature type, only 2 patients died during follow up time. Conclusion: The expression signature of TP53 has the ability to predict prognosis of early stage of lung adenocarcinoma regardless of EGFR status. Our data suggests that lung adenocarcinoma patients with mutant type of TP53 signature group may need careful observation and more intensive therapy after operation.

Abstract POSTER-CTRL-1204: Novel strategies for targeting high-grade serous ovarian cancer

Abstract High-grade serous ovarian carcinoma (HGSC) presents significant clinical and therapeutic challenges. Emerging data from The Cancer Genome Atlas (TCGA) have identified a number of new genetic aberrations but their functional significance and the role they play in early tumorigenesis remains to be determined. In addition, identifying the key genetic lesions responsible for tumor initiation and the specific cell of origin is a priority for ovarian cancer research. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent preclinical and clinical studies have suggested that there are additional sites of origin outside the ovary, namely fallopian tubal secretory epithelial cells (FTSECs). This new model of tumorigenesis has further identified novel entities in the fallopian tube epithelium that represent precursors to invasive carcinoma – the TP53 signature and serous tubal intraepithelial carcinoma (STIC). Identifying and characterizing the events leading to the development of TP53 signatures and STICs, the critical steps in their transition to malignancy, and novel methods for detecting this transition prior to cancer development are critical for cancer prevention and development of personalized approaches to therapy. We have successfully developed genetic models of de novo HGSC that originate in FTSECs and mimic the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. The murine tumors accurately recapitulate the histologic, immunophenotypic (CK-8, STMN1, PAX2, P53, Ki-67, WT1, and CA-125), and genomic alterations observed in human HGSC, thus providing a compelling argument for serous carcinogenesis originating in the FTSEC. Our models serve as a proof-of-concept that high-grade serous “ovarian” cancer can arise from the FTSEC and progress to metastatic disease via pre-invasive lesions, namely the STICs. We are currently using the Pax8-driven system to interrogate the role of TCGA genes that have been identified as being important for serous tumorigenesis. Successful completion of our studies will demonstrate that the fallopian tubal secretory epithelial cell is indeed a cell-of-origin for ovarian and pelvic serous carcinomas in vivo when using the most common key TCGA-based tumor drivers for BRCA and non-BRCA tumors, respectively. The first goal of our research is be to produce valid models for HGSC tumors. The second is to identify unique characteristics of early serous carcinogenesis in the tube that can be exploited for early detection. The third is to determine the causes of the earliest events preceding malignancy, which will enable more efficient methods of diagnostic imaging and cancer prevention with a focus on the distal fallopian tube. Furthermore, by using a combination of murine model studies and epidemiological data from patients, it will be important to determine if premenopausal women with BRCA mutations can be offered risk-reduction surgery in a multi-step procedure without undergoing surgical menopause and loss of fertility in their younger years. Citation Format: Ruth Perets, Gregory A Wyant, Anders W Ohman, Sunita R Setlur, Christopher P. Crum, Ronny Drapkin, Daniela M. Dinulescu. Novel strategies for targeting high-grade serous ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1204.

O1-15-2 - Tp53 Signature Predicts the Efficacy of Neoadjuvant Chemotherapy (Nac) of Breast Cancers

Background: We have reported that status of the TP53 mutation is predictable by expression profile of 33 genes (TP53 signature) in breast cancer and that the TP53 signature can predict overall survival and recurrent free survival of early breast cancer (Cancer Sci. 99: 324-32, 2008). The aim of this study is to determine whether the TP53 signature can also predict both the efficacy of NAC and the recurrence after surgery in breast cancer.Methods: An NAC cohort (E-GEOD-25066) that contains 508 patients with HER2 negative breast cancer is used. Among the genes previously used TP53 signature, 20 up-regulated and 5 down-regulated genes in breast cancer with TP53 mutation were selected and the TP53 status was determined by the ratio of the sum of expression values of 20 up-regulated genes to that of the 5 down-regulated genes. If the ratio (down / up) was less than 0.325, the tumor was determined as aTP53 mutant. If it was greater than or equal to 0.325, the tumor was determined aTP53 wild.Results: Fifty percent (255 of 508) of tumors was determined as a TP53 mutant. The pathological CR (pCR) rate is significantly higher in TP53 mutant tumor than in TP53 wild-type tumor (34.7% vs 5.4%). In Stage I and II patients (n = 280), recurrence free survival (RFS) was significantly better in patients with TP53 wild type tumor (P = 0.0018). Patients with TP53 mutant tumor not leading to pCR (mt / non-pCR) showed significantly worse RFS than the other patients (P < 0.001). In ER positive and triple negative subgroup, RFS were also worse in patients with mt / non-pCR.Conclusions: TP53 signature has the ability to predict the efficacy of NAC and recurrence after surgery in breast cancer. The TP53 signature was especially useful to predict the recurrence in combination with pCR status. Our data suggests that patients with TP53 mutant tumor not leading to pCR after NAC may need adjuvant chemotherapy after surgery to improve prognosis of these patients.

Prediction of breast cancer prognosis by gene expression profile of TP53 status

TP53 mutations are a poor prognostic factor in breast cancers. The present study sets out to identify the gene set that determines the expression signature of the TP53 status (TP53 signature) and to correlate it with clinical outcome. Using comprehensive expression analysis and DNA sequencing of the TP53 gene in 38 Japanese breast cancer patients, a gene set from differentially expressed genes was isolated, depending on the TP53 status. As independent external datasets, two published datasets were introduced for validation of TP53 status predictions (251 Swedish samples) and survival analysis (both the Swedish and 295 Dutch samples). Thirty-three gene sets were identified from microarray analysis. Predictive accuracy of the TP53 status by gene expression profiling was 83.3% in the test set (n = 12). TP53 signature has the ability to predict recurrence-free survival (RFS) of 29 stage I and stage II Japanese breast cancers (log rank, P = 0.032), and RFS, overall survival of two independently published datasets (log rank, both P < 0.0001). Multivariate analysis has shown that the TP53 signature an independent and significant prognostic factor with a hazard ratio (HR) for recurrence and survival in two external datasets (P < 0.0001). The TP53 signature is also a strong prognostic factor in the subgroups: estrogen-receptor positive, lymph node positive and negative, intermediate/high risk in St. Gallen criteria, and high risk in National Cancer Institute (NCI) criteria (log rank, P < 0.0001). TP53 signature is a reliable and independent predictor of the outcome of disease in operated breast cancer.