Anna Gumà

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Abstract P1-01-26: Clinical Implications of pN0 mol+ in Breast Cancer Patients

Introduction: Axillary lymph node involvement is the most significant prognostic factor in breast cancer patients. The real-time PCR (RT-PCR) appeared to be a sensitive method to diagnose the lymph node axillary stage, but the clinical relevance of pN0 (mol+) has not yet been established. We present the clinical characteristics of the subgroup of patients diagnosed as pN0 (mol+) and their clinical outcome after a mean follow-up of 72 months. Material & Methods: Between June 2000 and November 2006, 674 patients with T1-T3 primary invasive breast cancer and low probability of axillary lymph node involvement, were included in a prospective study of the molecular analyses of the sentinel lymph node (SLN) biopsy. Each SLN was bi-dissected; one half was snap frozen for subsequent molecular analysis, on the other half, routine pathological analyses was performed, including immunoassaying for cam 5.2 antibody. The molecular analyses was performed by RT-PCR using the gene marker KRT 19. Adjuvant treatment and clinical outcome has been recorded after a mean follow-up of 72 months. Results: 135 cases were staged as pN0 (mol+). Most of them corresponded to infiltrating ductal carcinoma (95%), 2.2% lobular, 1.5% colloid and 1.5% medullar. Nuclear grade: I in 5% of cases, II in 35% and III in 34% of them. By tumour stage, 1.5% were pT1a; 24% pT1b: 58% pT1c; 15% pT2 and 1.5% pT3. According to molecular subtypes, 73% of cases were luminal, 18.5% triple negative ones and 8.5% HER2 positive. All the patients except 5 ones received adjuvant systemic treatment: 41.5% hormonal therapy for at least 5 years; 32% chemotherapy followed by hormonotherapy and 18.5% chemotherapy, of those two patients received trastuzumab for 1 year. At the time of the analysis, there have been 4 local recurrences, 3 metastasic recurrences and 2 contra lateral ones. For survival analyses, 2 cases were excluded for presenting a previous breast cancer history, and one patient died after the last CMF from a septic shock. Of the 132 resting patients, 122 are free of relapse at the time of this analysis, the 3 patients with distant metastasis are on treatment for metastatic disease, 2 patients were death by other neoplastic diseases and 5 cases were death by other medical causes (4 cardiac and 1 respiratory failure). Survival rate for N0 mol+ was 94%, no specific breast cancer death have occurred at the present survival analyses. Conclusions: Tumours diagnosed as pN0 (mol+) presented clinical and molecular characteristics of worse prognosis than pN0 (mol-) and this is translated in a higher proportion of patients staged N0 (mol+) treated with chemotherapy than pN0 (mol-). Survival in this subgroup of patients is high in relation to the adjuvant treatment delivered. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-26.