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Goldin, Elena (2018) Predictive factors of non-sentinel axillary lymph nodes in breast cancer patients. Molecular markers of primary tumor and variability of patient's microenvironment. [Ph.D. thesis]

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Abstract (english)

Background: The management of breast cancer has changed dramatically over the past two decades, from radical mastectomy to breast conservative surgery. Axillary lymph node dissection (ALND) has moved from a complete dissection to a less invasive procedure, the sentinel lymph node biopsy (SNLB), which has less morbidity compared to ALND and is used to evaluate lymph node status. Patients with positive sentinel lymph node (SNL) undergo a complete ALND of axillary level I and II lymph nodes. This operation is burdened by relevant postoperative morbidity, such as upper limb lymphedema, wound complications, nerve injury, limited mobility, neuropathic pain, numbness and sensory loss. Axillary lymph node metastasis in early T stage breast cancer are often be confined within the SNL(s), which offers no information about the presence of additional non-SNL (NSNL) metastasis, which may not occur in 40% to 70% of cases. The identification of these low risk patients would prevent them the morbidity associated with a full ALND. In order to avoid unnecessary, highly morbid ALND, it has become imperative for breast surgeons to find diagnostic tool that can identify SNL positive patients at low risk of NSNL metastasis and also who can safely avoid an ALND.

Material and Methods: We analysed whether a panel of molecular genes, expressed in primary breast cancer patients who underwent SNLB for breast cancer at our Institution, could predict NSNL metastasis and the influence of polymorphisms of genes related to inflammatory and angiogenetic pathways (IL8 rs4073, VEGF-2 rs11133360) on axillary lymph node status and to predict NSNL metastasis.
Molecular Markers:
• Pilot study: We calculated the expression of a panel of genes in 24 frozen tissue samples from selected patients with positive SNL received ALND, 12 with negative NSNL and 12 with positive NSNL. We customized our PCR arrays that include the genes of RT2 Profiler ‘human modified breast cancer’ PCR arrays (SABiosciences) and 4 genes (NDUFA7, MERTK, FN1, PSMB6) obtained from a previous microarray study performed in our department (unpublished). These 88 genes are involved in tumor classification, signal transduction and pathways such as angiogenesis, adhesion, proteolysis, cell cycle, and apoptosis.
• Validation study: We evaluated the expression of five significant genes (THBS1, IGF1, ERBB2, GRB7, MGMT), obtained from previous pilot experiment, in 171 frozen tissue samples from primary breast cancer of patient, who underwent breast surgery and SNLB for invasive breast cancer, between 2000 to 2013 in 1st Surgical Clinic, with RT-PCR.
Polymorphisms (IL8 rs4073 VEGFr-2 rs11133360):
Genomic DNA was isolated from peripheral whole blood/buffy coat of 234 patients. 10 to 20 ng of DNA of each patient were used for TaqMan SNP genotyping assays (Applied Biosystems). Genotyping was performed by Real Time PCR using allelic discrimination in the 7300 RT PCR System (Applied Biosystems). Post run data were by 7300 SDS software (Applied Biosystems) and Automatic calls were assigned with approximately 99.8% quality analysed.


Results:
Molecular Markers: THBS1 (p:0.0012) and IGF1 (p:0,05) were statistically differently expressed between patients with positive SNLs and negative NSNLs and patients with positive SNLs and positive NSNLs. ERBB2, GRB7, MGMT were differently expressed between the two groups, not statistically significant (p:0,07; p:0,07; p:0,08), but we included in the validation study. The RT-PCR for THBS1, IGF1, ERBB2, GRB7, MGMT was performed in 171 patients. Only GRB7 level was differently expressed in the interest group of our research. The median expression level of GRB7 in patients with positive SNLB and negative NSNL was 3,14 ng/ul, in the group of patients with positive SNL and positive ALND the median level was 6,76 ng/ul (p:0,014). The other genes (IGF1, MGMT, ERBB2, THBS1) had a similar expression in these groups of patients
Vascular invasion (IV) and frozen section analysis were predictive factors of NSNLs status on univariate logistic regression analysis (p<0,05). Multivariate logistic regression analysis confirmed that GRB7 was an independent predictive factor of NSNLs in patients with positive SNLB (p:0,017). Moreover, frozen section analysis proved to be statistically different in the two groups on multivariate analysis (p:0,047).
The discrimination of the multivariable model was assessed with the area under the receiver ROC curve and AUC was 0,77.
Polymorphisms (IL8 rs4073 VEGFr-2 rs11133360): We considered two models for both polymorphism: dominant and recessive. When we analysed the correlation between the genotype and NSNLs status in patients with positive SNLs, no statistically significant results were obtained for both models. The two polymorphisms investigated were no predictive of axillary status in patients with positive SNL, but only IL8 rs4073, in recessive model, was significantly different between patients with axillary metastasis (N+) and patient with negative axillary status (N0)

Conclusion: Our data suggest that the expression level of GRB7 could be a predictive tool of axilla status in patients with positive SNLB and could help the surgeon to decide the better axillary surgery in this group of patients. The polymorphisms investigated are not predictive of NSNL status, but a homozygous woman for the allele A of the polymorphism IL-8 rs4073 has a probability 2.28 times greater than the rest of the sick population of developing axillary metastasis from breast cancer.

Abstract (italian)

Background: il trattamento del cancro alla mammella è cambiata radicalmente negli ultimi due decenni, si è passati dalla mastectomia radicale alla chirurgia conservativa. La dissezione linfonodale ascellare è stata sostituita da una procedura meno invasiva, la biopsia del linfonodo sentinella, che ha una minore morbilità rispetto alla linfadenectomia ascellare e viene utilizzata per valutare lo stato dei linfonodi. I pazienti con linfonodo sentinella positivo subiscono uno svuotamento di linfonodi ascellari di I e II livello. Questa operazione è gravata da una rilevante morbilità postoperatoria, come linfedema dell'arto superiore, complicanze della ferita, danno ai nervi, mobilità limitata, dolore neuropatico, intorpidimento e perdita sensoriale. Le metastasi linfonodali ascellari nel carcinoma mammario in stadio T precoce sono spesso confinate all'interno del linfonodo sentinella, che non offre informazioni sulla presenza di metastasi addizionali ai linfonodi non sentinella, 40% -70% dei casi . L'identificazione di questi pazienti a basso rischio di metastasi ai linfonodi non sentinella eviterebbe a questi pazienti una dissezione ascellare inutile. Al fine di evitare uno svuotamento ascellare non necessario è indispensabile trovare uno strumento diagnostico in grado di identificare i pazienti con linfonodo sentinella positivo a basso rischio di metastasi ai linfonodi non sentinella.

Materiale e metodi: Abbiamo valutato se l’espressione di un panel di geni in pazienti con carcinoma mammario sottoposte a biopsia del linfonodo sentinella presso la nostra U.O, potesse predire le metastasi ai linfonodi non sentinella e l'influenza di polimorfismi di geni correlati a vie infiammatorie e angiogenetiche (IL8 rs4073, VEGF-2 rs11133360) sullo stato linfonodale ascellare e per predire le metastasi ai linfonodi non sentinella.
Marcatori molecolari:
• Studio pilota: abbiamo calcolato l'espressione di un pannello di geni in 24 campioni di tessuto congelato da pazienti selezionati con linfonodo sentinella positivo sottoposte anche a linfadenectomia ascellare, 12 con linfonodi non sentinella negativi e 12 con linfonodi non sentinella positivo. Abbiamo personalizzato i nostri array di PCR che includono i geni delle sequenze PCR del cancro della mammella RT2 Profiler (SABiosciences) e 4 geni (NDUFA7, MERTK, FN1, PSMB6) ottenuti da uno studio precedente di microarray eseguito nel nostro dipartimento (non pubblicato). Questi 88 geni sono coinvolti nella classificazione del tumore, nella trasduzione del segnale e in percorsi come l'angiogenesi, l'adesione, la proteolisi, il ciclo cellulare e l'apoptosi.
• Studio di validazione: abbiamo valutato l'espressione di cinque geni significativi (THBS1, IGF1, ERBB2, GRB7, MGMT), ottenuti dal precedente esperimento pilota, in 171 campioni di tessuto congelato da carcinoma mammario di paziente, sottoposte a chirurgia mammaria e biopsia del linfonodo sentinella per cancro alla mammella, tra il 2000 e il 2013 nella nostra UO, con RT-PCR.

Polimorfismi (IL8 rs4073 VEGFr-2 rs11133360):
Il DNA genomico è stato isolato dal sangue periferico / buffy coat di 234 pazienti. Sono stati utilizzati da 10 a 20 ng di DNA di ciascun paziente per i saggi di genotipizzazione di TaqMan SNP (Applied Biosystems). La genotipizzazione è stata eseguita mediante Real Time PCR utilizzando la discriminazione allelica nel sistema PCR RT 7300 (Applied Biosystems). I dati post-esecuzione sono stati forniti dal software SDS 7300 (Applied Biosystems) e le chiamate automatiche sono state assegnate con una qualità analizzata del 99,8% circa.

Risultati:
Marcatori molecolari: THBS1 (p: 0,0012) e IGF1 (p: 0,05) sono statisticamente differentemente espressi tra pazienti con linfonodi sentinella positivi e linfonodi non sentinella negativi e pazienti con linfonodi sentinella positivi e linfonodi non sentinella positivi. ERBB2, GRB7, MGMT sono differentemente espressi tra i due gruppi, ma in maniera non statisticamente significativa (p: 0,07; p: 0,07; p: 0,08), ma li abbiamo inclusi nello studio di convalida. La RT-PCR per THBS1, IGF1, ERBB2, GRB7, MGMT è stata eseguita in 171 pazienti. Solo il livello di GRB7 è espresso in modo diverso nel gruppo di interesse della nostra ricerca. Il livello di espressione medio di GRB7 in pazienti con linfonodo sentinella positivo e linfonodo non sentinella negativo era 3,14 ng / ul, nel gruppo di pazienti con linfonodo sentinella positivo e svuotamento ascellare positivo il livello mediano era di 6,76 ng / ul (p: 0,014). Gli altri geni (IGF1, MGMT, ERBB2, THBS1) hanno un'espressione simile in questi gruppi di pazienti
L'invasione vascolare (IV) e l'analisi della sezione congelata sono fattori predittivi dello stato delle NSNL sull'analisi di regressione logistica univariata (p <0,05). L'analisi di regressione logistica multivariata ha confermato che GRB7 è un fattore predittivo indipendente di stato dei linfonodi non sentinella in pazienti con linfonodo sentinella positivo (p: 0,017). Inoltre, l'analisi della sezione congelata si è dimostrata statisticamente diversa nei due gruppi sull'analisi multivariata (p: 0,047).
La discriminazione della multivariata è stata valutata con l'area sotto la curva ROC ricevente e l'AUC è 0,77.

Polimorfismi (IL8 rs4073 VEGFr-2 rs11133360): Abbiamo considerato due modelli per entrambi i polimorfismi: dominante e recessivo. Quando abbiamo analizzato la correlazione tra lo stato genotipo e lo stato dei linfonodi non sentinella in pazienti con linfonodi sentinella positivi, non sono stati ottenuti risultati statisticamente significativi per entrambi i modelli. I due polimorfismi studiati non sono predittivi dello stato ascellare in pazienti con linfonodo sentinella positivo, ma solo IL8 rs4073, nel modello recessivo, è significativamente differente tra pazienti con metastasi ascellari (N +) e pazienti con stato ascellare negativo (N0)

Conclusione: I nostri dati suggeriscono che il livello di espressione di GRB7 potrebbe essere uno strumento predittivo dello stato ascellare in pazienti con linfonodo sentinella positivo e potrebbe aiutare il chirurgo a decidere la migliore chirurgia in questo gruppo di pazienti. I polimorfismi studiati non sono predittivi dello stato di NSNL, ma una donna omozigote per l'allele A del polimorfismo IL-8 rs4073 ha una probabilità di 2,28 volte maggiore rispetto al resto della popolazione malata di sviluppare metastasi ascellari se affetta da tumore della mammella.

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EPrint type:Ph.D. thesis
Tutor:Nitti, Donato
Ph.D. course:Ciclo 30 > Corsi 30 > ONCOLOGIA CLINICA E SPERIMENTALE E IMMUNOLOGIA
Data di deposito della tesi:09 January 2018
Anno di Pubblicazione:09 January 2018
Key Words:breast predictive factors
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/18 Chirurgia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:10602
Depositato il:26 Oct 2018 08:42
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