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Gagno, Sara (2015) Innovative strategies for tailoring therapy in cancer patient: pharmacogenetics and hormone therapy personalization in metastatic or locally advanced breast cancer patients treated with Exemestane. [Ph.D. thesis]

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Abstract (english)

Background: Response to chemotherapeutic agents is highly variable among patients both in terms of efficacy and tolerability; consequently personalization of drug therapy is one of the main objective in cancer treatment in order to reduce adverse drug reactions (ADRs), improve efficacy while decreasing the costs of treatments. Many factors account for inter-individual differences. Among them, patient’s genetic background has attracted interest for personalization of drug therapy (Pharmacogenetics).
Breast cancer (BC) is the female most frequently diagnosed malignancy and the primary cause of cancer-related death among females with 1.380.000 new cases and 458.000 deaths worldwide registered in 2008. Estrogen receptors (ER) are over-expressed in around 80% of breast cancer cases and ER-positive (ER+) cancer cells depend on estrogens for their growth. In postmenopausal women estrogens can derive only from androgens through an aromatization reaction. Aromatase (CYP19A1) is a key enzyme in this process and, for this reason, is the target of many inhibitors drugs, including exemestane. Anti-aromatase treatments represent the current corner-stone of ER+ BC therapy in postmenopausal women.
Exemestane is a steroidal irreversible third generation aromatase inhibitor (AI) which determines the inactivation of the enzyme, resulting in estrogen synthesis inhibition and deprivation.
Exemestane is used in adjuvant setting for ER+ early stage invasive BC and for the treatment of advanced stage BC progressed to a previous anti-estrogen therapy.
Several germ line variations (polymorphisms) have been described in genes involved either in estrogens activity and metabolism or in the pharmacokinetics of exemestane.

Aims: this PhD thesis had a dual aim:
* setting up a pharmacogenetic method to analyze estrogen and exemestane-related polymorphisms (Single Nucleotide Polymorphisms (SNPs) and Short Tandem Repeats (STRs)),
* determining the predictive and prognostic value of these polymorphisms in postmenopausal metastatic or locally advanced ER+ BC patients (Response Rate (RR), Clinical Benefit (CB), Time To Progression (TTP) and Overall Survival (OS)).
Fifteen polymorphisms in genes involved estrogens synthesis (CYP17A1 and CYP19A1), activity (ESR1, ESR2 and RIZ1) and metabolism (CYP1B1, UGT1A1 and COMT) as well as genes implicated in the metabolic pathway of exemestane (CYP3A4 and CYP3A5) were investigated.
We considered the CYP19A1_Ex11_410A/C (rs4646) SNP in the 3’ untraslated region (3'UTR) of the aromatase gene, previously associated to a better disease-free survival (DFS) (Colomer et al., 2008) in patients treated with the AI, letrozole, and to a better OS in patients treated with another AI, anastrozole (Liu et al., 2013). However, the role of this polymorphism has not yet been clearly defined. Other CYP19A1 polymorphisms analyzed were: CYP19A1_47T/C (rs700519), CYP19A1_1558T/C (rs10046) and CYP19A1_(TTTA)n (rs60271534), along with a SNP on the CYP17A1 gene (CYP17A1_27A/G (rs743572)), coding for another enzyme responsible for estrogens synthesis.
Additionally, we investigated:
* polymorphisms on estrogens receptors: ESR1: ESR1_497T/C (rs2234693), and ESR1_256A/G (rs9340799); ESR2: ESR2_1082A/G (rs1256049), and ESR2_1730A/G (rs4986938); RIZ1: RIZ1_delP704 (rs2308040);
* polymorphisms on estrogens metabolizing enzymes: CYP1B1: CYP1B1*3_4326G/C (rs1056836), UGT1A1: UGT1A1*28_ TA(6/7) (rs8175347) and COMT: COMT_12A/G (rs4680);
* polymorphisms on enzymes involved in the oxidative metabolism of exemestane: CYP3A4: CYP3A4*1B_-392A/G (rs2740574) and CYP3A5: CYP3A5*3_6986A/G (rs776746).

Methods: genetic analyses were conducted in a group of 275 ER+ metastatic or locally advanced BC patients treated with exemestane as first line hormone therapy.
Patients were subjected to blood sampling before the beginning of therapy. DNA was extracted from whole blood, and then amplified by Polymerase Chain Reaction (PCR).
Four methods for polymorphisms genotyping were set up and developed: Pyrosequencing, TaqMan® Allelic Discrimination Assay, Automated Fragment Analysis and Illumina GoldenGate Assay.
Statistical associations between genetic determinants and clinical outcome were assessed by the two-sided Fisher’s Exact Test (associations between genotypes and clinical responses) and the Kaplan-Meier product-limit method with the log-rank test statistic (associations between polymorphisms and TTP/OS).

Results: For each polymorphism the most appropriate technique, based on the best result obtained in the setting up process, was chosen. As a result:
* three SNPs were investigated with Pyrosequencing: CYP19A1_47T/C (rs700519), CYP3A4*1B_-392A/G (rs2740574), and RIZ1_delP704 (rs2308040);
* ten SNPs were genotyped with TaqMan® Allelic Discrimination Assay: CYP19A1_Ex11+410A/C (rs4646), CYP19A1_1558T/C (rs10046), CYP3A5*3_6986A/G (rs776746), COMT_12A/G (rs4680), ESR1_497T/C (rs2234693), ESR1_256A/G (rs9340799), ESR2_1082A/G (rs1256049), ESR2_1730A/G (rs4986938), CYP17A1_27A/G (rs743572) and CYP1B1*3_4326G/C (rs1056836);
* two STR were analyzed with Automated Fragment Analysis: CYP19A1_(TTTA)n (rs60271534) and UGT1A1*28_ TA(6/7) (rs8175347)
* twelve of the above mentioned polymorphisms were additionally analyzed by Illumina GoldenGate Assay as positive controls. The results obtained by this validation process was a 100% accordance within the genotypes obtained.
Among the polymorphisms investigated, a statistically significant association was observed for CYP1B1, the gene encoding for the enzyme which catalyze the phase I estrogens oxidative metabolism. The variant (G) allele of CYP1B1*3_4326G/C (rs1056836) was significantly associated with clinical response to exemestane (RR, ORGG = 2.91, 95% CI = 5.88 – 1.25, p = 0.0039; according to the two-sided Fisher’s exact test). The same variant allele was also significantly associated with the TTP and OS (TTP, dominant model: HR CG+GG= 0.66, 95% CI = 0.50 – 0.87, p = 0.0037; OS, dominant model = HR CG+GG= 0.66, 95% CI = 0.46 – 0.95, p = 0.023, according to the log-rank test) meaning that patients carrying at least one variant allele (G) not only showed a better clinical response, but experienced also a later progression and a longer survival than wild type patients.
Regarding the aromatase gene (CYP19A1 gene), the only association found, even if marginal, was between CYP19A1_1558T/C (rs10046) SNP and TTP (HRCC recessive model=1.4, 95%CI = 1.04 – 1.89, p = 0.028). Conversely, we did not find any significant association between CYP19A1_Ex11_410A/C (rs4646) SNP, (the main objective of the study) and RR, CB, TTP or OS, respectively.
Concerning aromatase gene polymorphisms, we were able to describe a new genetic variant for the CYP19A1_(TTTA)n (rs60271534) STR in intron 4. Genetic databases and literature report that the number of repeats varies from 7 to 13, but we found a still not described 14 (TTTA) repeats allele.

Conclusions: in conclusion, this thesis work allowed defining a new molecular marker, CYP1B1*3_4326G/C (rs1056836) SNP, with a predictive and prognostic value for the exemestane-based treatment of postmenopausal ER+ metastatic or locally advanced BC patients. This indicates that, once validated, this marker could potentially be employable in the daily clinical oncology practice as a tool which may allow the identification of patients more likely to be responsive to treatment by a simple genetic evaluation from peripheral blood, performed prior to therapy. In addition, we described a new genetic variant in the aromatase gene.

Abstract (italian)

Introduzione: La risposta agli agenti chemioterapici è altamente variabile tra i pazienti sia per quanto riguarda l’efficacia che la tollerabilità, di conseguenza la personalizzazione della terapia è uno dei principali obiettivi della ricerca in campo oncologico con l’obiettivo di ridurre le reazioni avverse al farmaco, migliorarne l’efficacia e nel contempo contenerne i costi.
I fattori responsabili della variabilità interindividuale sono molteplici. Tra questi, il background genetico dei pazienti ha attratto interesse per la personalizzazione della terapia (Farmacogenetica).
Il carcinoma mammario (breast cancer - BC) rappresenta la neoplasia più frequentemente diagnosticata e la prima causa di morte collegata al cancro tra le donne. Nel 2008 sono stati registrati, a livello mondiale, 1.380.000 nuovi casi e 458.000 morti a causa del cancro della mammella.
Il recettore degli estrogeni (estrogen receptor - ER) risulta iper-espresso in circa l’80% dei casi di BC e le cellule cancerose positive al ER (ER+) dipendono dagli estrogeni per la loro crescita. Nelle donne in menopausa, gli estrogeni derivano unicamente dagli androgeni attraverso una reazione di aromatizzazione. L’aromatasi (CYP19A1) è un enzima chiave in questo processo e, per questa ragione, è diventato il target di numerosi farmaci inibitori, compreso exemestane. Il trattamento anti-aromatasi rappresenta attualmente il cardine della terapia del ER+ BC nelle donne in menopausa.
Exemestane è un inibitore irreversibile dell’aromatasi (AI) di terza generazione e di tipo steroideo che determina l’inattivazione dell’enzima, provocando quindi l’inibizione della sintesi estrogenica.
Exemestane è un farmaco impiegato in assetto adiuvante per il ER+ BC invasivo allo stadio precoce ed in assetto avanzato se la malattia è progredita dopo una precedente terapia anti-estrogenica.
Sono state descritte numerose variazioni genetiche germinali (polimorfismi) in geni coinvolti sia nell’attività e metabolismo degli estrogeni che nella farmacocinetica di exemestane.

Obiettivi: questa tesi di dottorato ha avuto un duplice obiettivo:
* mettere a punto un metodo di indagine farmacogenetica per analizzare polimorfismi correlati ad estrogeni ed exemestane (polimorfismi a singolo nucleotide – SNPs e microsatelliti (short tandem repeats) - STRs)
* determinare il ruolo predittivo e prognostico di tali polimorfismi come biomarcatori di efficacia del trattamento a base di exemestane, in termini di Response Rate (RR), Clinical Benefit (CB), tempo alla progressione (TTP) e sopravvivenza globale (OS).
Sono stati considerati quindici polimorfismi in geni coinvolti nella sintesi (CYP17A1 e CYP19A1), attività (ESR1, ESR2 e RIZ1) e metabolismo (CYP1B1, UGT1A1 e COMT) degli estrogeni insieme a geni implicati nel pathway metabolico di exemestane (CYP3A4 e CYP3A5).
Come obiettivo primario dello studio clinico è stato considerato lo SNP CYP19A1_Ex11_410A/C (rs4646) della regione non 3’ tradotta (3’ untraslated region - 3’UTR) del gene dell’aromatasi, già in precedenza associato ad una migliore sopravvivenza libera da malattia (disease free servival – DFS) (Colomer et al., 2008) in pazienti trattate con l’AI letrozolo e con la miglior OS in pazienti trattate con un altro AI, l’anastrozolo (Liu et al., 2013). Ciononostante, il ruolo di questo polimorfismo non è stato ancora chiaramente definito. Sono stati analizzati anche altri polimorfismi del gene CYP19A1 (CYP19A1_47T/C (rs700519), CYP19A1_1558T/C (rs10046) e CYP19A1_(TTTA)n (rs60271534)) insieme ad uno SNP nel gene CYP17A1(CYP17A1_27A/G (rs743572)), codificante per un altro enzima responsabile della sintesi degli estrogeni.
Inoltre, sono stati indagati polimorfismi dei geni codificanti per:
* i recettori degli estrogeni: ESR1: ESR1_497T/C (rs2234693), e ESR1_256A/G (rs9340799); ESR2: ESR2_1082A/G (rs1256049), e ESR2_1730A/G (rs4986938); RIZ1: RIZ1_delP704 (rs2308040);
* gli enzimi deputati al metabolismo degli estrogeni: CYP1B1: CYP1B1*3_4326G/C (rs1056836), UGT1A1: UGT1A1*28_ TA(6/7) (rs8175347) e COMT: COMT_12A/G (rs4680);
* gli enzimi responsabili del metabolismo ossidativo di exemestane: CYP3A4: CYP3A4*1B_-392A/G (rs2740574) e CYP3A5: CYP3A5*3_6986A/G (rs776746).

Metodi: le analisi genetiche sono state condotte in un gruppo di 275 pazienti affetti da ER+ BC metastatico o localmente avanzato trattate con exemestane come prima linea di trattamento ormonale. Ai pazienti è stato effettuato un prelievo ematico prima dell’inizio della terapia. Il DNA è stato poi estratto dal campione di sangue intero ed amplificato tramite la reazione a catena della polimerasi (PCR).
Per le analisi genetiche sono state messe a punto quattro tecniche di genotipizzazione: Pyrosequencing, Saggio di Discriminazione Allelica mediante sonde TaqMan®, Analisi dei Frammenti Automatizzata ed il saggio GoldenGate di Illumina.
Sono state valutate le associazioni statistiche tra i determinanti genetici e l’outcome clinico dei pazienti attraverso il Test Esatto di Fisher a due vie per l’associazione di polimorfismi e risposta clinica e attraverso lo stimatore del prodotto limite di Kaplan Meier e il test dei ranghi logaritmici per l’associazione tra polimorfismi e TTP/OS.

Risultati: per ogni polimorfismo è stata scelta la tecnica di indagine molecolare più appropriata a seconda del miglior risultato ottenuto durante la fase di messa a punto delle metodologie. Di conseguenza:
* tre SNPs sono stati analizzati con il Pyrosequencing: CYP19A1_47T/C (rs700519), CYP3A4*1B_-392A/G (rs2740574), e RIZ1_delP704 (rs2308040);
* dieci SNPs sono stati genotipizzati con il saggio di Discriminazione Allelica mediante sonde TaqMan®: CYP19A1_Ex11+410A/C (rs4646), CYP19A1_1558T/C (rs10046), CYP3A5*3_6986A/G (rs776746), COMT_12A/G (rs4680), ESR1_497T/C (rs2234693), ESR1_256A/G (rs9340799), ESR2_1082A/G (rs1256049), ESR2_1730A/G (rs4986938), CYP17A1_27A/G (rs743572) e CYP1B1*3_4326G/C (rs1056836);
* due STR sono stati esaminati attraverso l’Analisi dei Frammenti Automatizzata: CYP19A1_(TTTA)n (rs60271534) e UGT1A1*28_ TA(6/7) (rs8175347);
* i campioni analizzati per dodici dei sopraccitati polimorfismi sono stati, inoltre, inclusi nel saggio Illumina GoldenGate come controlli positivi. Il risultato di questo processo di validazione è stata una concordanza del 100% tra i genotipi ottenuti con questa tecnica e quelli derivanti dalle precedenti indagini.
Tra i polimorfismi analizzati, è stata osservata un’associazione statisticamente significativa per CYP1B1, gene codificante per l’enzima responsabile del metabolismo ossidativo di prima fase degli estrogeni. L’allele variante G del polimorfismo CYP1B1*3_4326G/C (rs1056836) è stato significativamente associato con la risposta clinica ad exemestane (RR, ORGG = 2.91, 95% CI = 5.88 – 1.25, p = 0.0039; secondo il Test Esatto di Fisher a due vie). Lo stesso allele variante è stato significativamente associato anche al TTP e alla OS (TTP, modello dominante: HR CG+GG= 0.66, 95% CI = 0.50 – 0.87, p = 0.0037; OS, modello dominante = HR CG+GG= 0.66, 95% CI = 0.46 – 0.95, p = 0.023, secondo il test dei ranghi logaritmici). Questo significa che pazienti portatori di almeno un allele G non solo hanno dimostrato una miglior risposta clinica al trattamento ma hanno anche avuto una progressione più tardiva ed una sopravvivenza più lunga dei pazienti wild type.
Per quanto riguarda il gene dell’aromatasi, l’unica associazione riscontrata, anche se marginale, riguarda il polimorfismo CYP19A1_1558T/C (rs10046) il cui allele variante C che è stato associato ad un ridotto TTP (HRCC modello recessivo =1.4, 95%CI = 1.04 – 1.89, p = 0.028, secondo il Test Esatto di Fischer a due vie).
Al contrario, non è stata riscontrata alcuna associazione significativa tra lo SNP CYP19A1_Ex11_410A/C (rs4646), obiettivo principale dello studio, e RR, CB, TTP o OS.
Riguardo i polimorfismi del gene dell’aromatasi, siamo stati in grado di descrivere una nuova variante genetica per il polimorfismo STR CYP19A1_(TTTA)n (rs60271534) dell’introne 4. Le banche dati genetiche e la letteratura riportano che il numero di ripetizioni della quadripletta TTTA vari tra 7 e 13, ma nel nostro studio è stato individuato un allele, finora mai descritto, con 14 ripetizioni.

Conclusioni: in conclusione, questo lavoro di tesi ha permesso di definire un nuovo biomarcatore molecolare, lo SNP CYP1B1*3_4326G/C (rs1056836), con un valore predittivo e prognostico per il trattamento a base di exemestane in pazienti affetti da ER+ BC, metastatico o localmente avanzato.
Questo presuppone che, se validato, questo biomarcatore potrebbe potenzialmente essere impiegato nella pratica clinica oncologica quotidiana come strumento che potrebbe aiutare ad identificare i pazienti che hanno una maggiore probabilità di risposta all’exemestane tramite una semplice valutazione genetica da sangue periferico da effettuarsi prima della terapia. Inoltre, è stata descritta una nuova variante genetica del gene dell’aromatasi.

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EPrint type:Ph.D. thesis
Tutor:Giusti, Pietro
Data di deposito della tesi:28 January 2015
Anno di Pubblicazione:28 January 2015
Key Words:farmacogenetica exemestane carcinoma mammella polimorfismo / pharmacogenetics exemestane breast cancer polymorphism
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:7683
Depositato il:12 Nov 2015 10:15
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