Phd in TRANSATIONAL MEDICINE AND ONCOLOGY

Thesis title: Nuove frontiere nel trattamento dell’atrofia vulvo-vaginale nelle pazienti oncologiche: studio delle modificazioni rigenerative e del miglioramento della qualità di vita mediante laser cervico-vaginale.

Genitourinary syndrome of menopause (GSM) is a chronic and progressive condition primarily caused by estrogen deprivation of the tissues of the urogenital unit. In patients with breast cancer, particularly those undergoing adjuvant endocrine therapy, pharmacologically induced hypoestrogenism frequently leads to severe forms of vulvovaginal atrophy, associated with pain, dyspareunia, urinary symptoms, and a significant impairment in quality of life. In this population, the use of local estrogen therapies remains controversial, highlighting the need for effective and biologically safe non-hormonal therapeutic strategies. In this context, vaginal laser technologies have emerged as a promising regenerative approach, although the molecular mechanisms underlying the tissue response remain incompletely understood. The present prospective experimental study evaluated the clinical efficacy and molecular impact of treatment with a non-ablative diode vaginal laser (1470 nm) in 63 women affected by GSM, including 40 patients with a history of breast cancer and 23 women with physiological menopause. All patients underwent four treatment sessions and were evaluated before therapy (T0) and four weeks after the final application (T5). Clinical, symptomatic, and microbiological assessments were performed. Clinical outcomes were evaluated using the Vaginal Health Index (VHI) and the Visual Analog Scale for pain (VAS), while symptom assessment was conducted using the validated questionnaires Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), and the International Consultation on Incontinence Questionnaire – Urinary Incontinence Short Form (ICIQ-UI SF) at baseline (T0) and after treatment completion (T5). In a subgroup of patients, molecular analysis was also performed at T0 and T5 using RT-qPCR to assess the expression of extracellular matrix genes COL1A1, COL3A1, and the microRNA miR-200c. Treatment was associated with a significant clinical improvement in GSM symptoms. Vaginal pain assessed by VAS significantly decreased from 5.26 ± 2.13 to 3.37 ± 1.68 (Δ −1.89; p < 0.0001). In parallel, sexual function (FSFI) significantly increased from 20.84 ± 14.50 to 34.48 ± 11.10 (Δ +13.63; p < 0.0001), while sexual distress (FSDS) decreased from 23.06 ± 14.22 to 10.10 ± 7.00 (Δ −12.97; p < 0.0001). The severity of urinary symptoms (ICIQ-UI SF) also showed a significant reduction, decreasing from 3.30 ± 4.52 to 2.16 ± 2.57 (Δ −1.14; p = 0.001). These clinical improvements were comparable between oncological and non-oncological patients. Molecular analysis revealed increased expression of COL1A1 and COL3A1 in the analyzable samples, suggesting activation of neocollagenesis and stromal remodeling processes consistent with a regenerative response of the vaginal mucosa. Furthermore, a significant modulation of miR-200c expression was observed after treatment (p = 0.0014). A particularly interesting finding emerged from the analysis stratified by tumor subtype: miR-200c upregulation was significant in patients with luminal and HER2-positive breast cancers (median pre-treatment 1.010, median post-treatment 2.600; p = 0.042), whereas no significant variation was observed in patients with triple-negative breast cancer (median pre-treatment 0.994, median post-treatment 1.057; p = 0.313). This difference suggests a possible interaction between the epithelial plasticity programs characteristic of different tumor subtypes and the regenerative response induced by laser treatment. Overall, these results suggest that non-ablative vaginal laser treatment induces coordinated epithelial–stromal remodeling associated with a significant clinical improvement in GSM symptoms. The differential modulation of miR-200c according to tumor subtype further introduces a biologically relevant translational element, suggesting that the molecular response to regenerative treatments may be influenced by the biological characteristics of the primary tumor.