A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study

Currently there are no reliable biomarkers to predict outcome of exemestane treatment. We designed a prospective study to investigate whether constitutive genetic background might affect response to therapy. In a population of 302 advanced breast cancer patients treated with exemestane we showed that a 5-polymorphism-based genetic score could be used to identify patients with different risks of progression and death.Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients

Background: Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (RT) dosage and cotreatment with oxaliplatin. Methods: Thirty germ-line SNPs in twenty-one genes were selected according to a pathway-based approach. Genetic analyses were performed on 280 LARC patients who underwent fluoropyrimidine-based CRT. The potential predictive role of these SNPs in determining pathological tumor response was tested in Group 1 (94 patients undergoing also oxaliplatin), Group 2 (73 patients treated with high RT dosage), Group 3 (113 patients treated with standard RT dosage), and in the pooled population (280 patients). Results: Nine new predictive biomarkers were identified in the three groups. The most promising one was rs3136228-MSH6 (p = 0.004) arising from Group 3. In the pooled population, rs1801133-MTHFR showed only a trend (p = 0.073). Conclusion: This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses

Pharmacogenomics of miRNA for personalized anticancer treatment

Pharmacogenetics (PGx) aims at the definition of predictive and prognostic genetic biomarkers that can help clinicians in treatment tailoring. In this thesis, we explored two emerging topics in PGx: SNPs affecting the activity and maturation of a class of non coding RNAs, microRNAs (miRNAs), and immunogenetics. Genetic analyses were performed by a medium throughput technology, Veracode technology (Illumina). The clinical model of this study is represented by the locally advanced rectal cancer (LARC). Specifically, the main two aims of this study were: 1. the identification of predictive biomarkers of pathological response to neoadjuvant treatment in LARC patients, defined in terms of tumour regression grade (TRG); 2. the identification of biomarkers of disease free survival (DFS) and overall survival (OS) in LARC patients. To find an answer to these questions, we analyzed two panels of SNPs, selected according to bioinformatic analysis and literature data, on a group of 280 LARC patients homogeneously treated with fluoropyrimidines-based chemoradiotherapy in neo-adjuvant setting. In the first part of this project, we analyzed a panel of 144 SNPs potentially involved in miRNA maturation and activity. With a quite complex statistical strategy, we identified 5 new predictive biomarkers of response to neoadjuvant treatment. Specifically, DROSHA-rs10719 and SMAD3-rs17228212 were unfavourable predictive biomarkers (p=0.0274, p=0.0049), while SMAD3-rs744910, SMAD3-rs745103, and TRBP-rs6088619 showed an opposite effect (p=0.0153, p=0.0471, p=0.0125). Moreover, in patients with complete pathological response (TRG1), SMAD3-rs745103 was significantly associated with DFS (p=0.011). This study underlines the potential key role of SMAD3, factor involved not only in miRNA maturation but also in inflammation and in particular in TGF\u3b2 pathway, that is crucial in cancer progression and treatment response. Bearing in mind this interesting results and the huge amount of literature data addressing the high potentiality of immunogenetics in oncology, we analyzed a panel of 192 SNPs in genes involved in immune response in the same group of 280 LARC patients. We investigated another clinical end-point, the 2-year disease-free survival (2yDFS), because it is a strong prognostic biomarker of OS. Firstly, we identified 4 SNPs significantly associated with the 2yDFS. Two of them are located in IL17F (rs641701: OR=5.84, 95% CI=1.52-22.45, p=0.010; rs9463772: OR=3.56, 95% CI=1.22-10.35, p=0.020) and the other ones in STAT3 (rs8069645: OR=0.36, 95% CI=0.13-0.99, p=0.048; rs9867701: OR=3.00, 95% CI=1.09-8.30, p=0.034). Secondly, we studied the potential association of these 4 SNPs with the 10 years overall survival (OS). Interestingly, 3 SNPs remained significant and two of them are located in IL17F gene (IL17F-rs641701: OR=3.23, 95% CI=1.50-6.95, p=0.003; IL17F-rs9463772 OR=2.89, 95% CI=1.49-5.61, p=0.002, and STAT3-rs8069645 OR=0.50, 95% CI=0.25-0.98, p=0.044). We tested these associations in a validation group of 63 LARC patients who underwent radical surgery and adjuvant treatment based on fluoropyrimidines. Surprisingly, IL17F-rs9463772 is still significantly associated with OS (p=0.045), thus we can conclude that this is really a strong prognostic biomarker. To conclude, we performed 2 different PGx projects that led us to identify different predictive and prognostic biomarkers in LARC patients. These data, if confirmed in larger studies, will help clinicians to personalize patients treatment and management

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients

Background: Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (RT) dosage and cotreatment with oxaliplatin. Methods: Thirty germ-line SNPs in twenty-one genes were selected according to a pathway-based approach. Genetic analyses were performed on 280 LARC patients who underwent fluoropyrimidine-based CRT. The potential predictive role of these SNPs in determining pathological tumor response was tested in Group 1 (94 patients undergoing also oxaliplatin), Group 2 (73 patients treated with high RT dosage), Group 3 (113 patients treated with standard RT dosage), and in the pooled population (280 patients). Results: Nine new predictive biomarkers were identified in the three groups. The most promising one was rs3136228-MSH6 (p = 0.004) arising from Group 3. In the pooled population, rs1801133-MTHFR showed only a trend (p = 0.073). Conclusion: This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses

Impact of DNA repair gene polymorphisms on the risk of biochemical recurrence after radiotherapy and overall survival in prostate cancer

The identification of biomarkers of biochemical recurrence (BCR) in prostate cancer (PCa) patients undergoing radiotherapy (RT) represents an unanswered clinical issue. The primary aim of this study was the definition of new genetic prognostic biomarkers in DNA repair genes (DRGs), considering both BCR and overall survival (OS) as clinical end-points. The secondary aim was to explore the potential clinical impact of these genetic variants with the decision curve analysis (DCA) and the sensitivity analysis. We analyzed 22 germline polymorphisms in 14 DRGs on 542 Caucasian PCa patients treated with RT as primary therapy. Significant associations were further tested with a bootstrapping technique. According to our analyses, ERCC2-rs1799793 and EXO1-rs4149963 were significantly associated with BCR (p = 0.01 and p = 0.01, respectively). Moreover, MSH6-rs3136228 was associated with a worse OS (p = 0.04). Nonetheless, the DCA and the sensitivity analyses gave no ultimate response about the clinical impact of such variants. This study highlights the potential prognostic role of polymorphisms in DRGs for PCa, paving the way to the introduction of not invasive tools for the personalization of patients management. Nonetheless, other prospective studies are necessary to ultimately clarify the clinical impact of pharmacogenetics in PCa

rs4143815-PDL1, a New Potential Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy

Up to 30&ndash;50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients&rsquo; treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value &lt; 0.05, q-value &lt; 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41&ndash;0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26&ndash;1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40&ndash;0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16&ndash;0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa

Polysaccharides for the delivery of antitumor drugs

Among the several delivery materials available so far, polysaccharides represent very attractive molecules as they can undergo a wide range of chemical modifications, are biocompatible, biodegradable, and have low immunogenic properties. Thus, polysaccharides can contribute to significantly overcome the limitation in the use of many types of drugs, including anti-cancer drugs. The use of conventional anti-cancer drugs is hampered by their high toxicity, mostly depending on the indiscriminate targeting of both cancer and normal cells. Additionally, for nucleic acid based drugs (NABDs), an emerging class of drugs with potential anti-cancer value, the practical use is problematic. This mostly depends on their fast degradation in biological fluids and the difficulties to cross cell membranes. Thus, for both classes of drugs, the development of optimal delivery materials is crucial. Here we discuss the possibility of using different kinds of polysaccharides, such as chitosan, hyaluronic acid, dextran, and pullulan, as smart drug delivery materials. We first describe the main features of polysaccharides, then a general overview about the aspects ruling drug release mechanisms and the pharmacokinetic are reported. Finally, notable examples of polysaccharide-based delivery of conventional anti-cancer drugs and NABDs are reported. Whereas additional research is required, the promising results obtained so far, fully justify further efforts, both in terms of economic support and investigations in the field of polysaccharides as drug delivery materials