Tmb in nsclc: A broken dream?

none3noAlthough immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.openBravaccini S.; Bronte G.; Ulivi P.Bravaccini, S.; Bronte, G.; Ulivi, P

Impressive long-term response with chemo-endocrine therapy in a premenopausal patient with metastatic breast cancer: A case report

RATIONALE: Patients with, or who develop, metastatic breast cancer have a 5-year relative survival of about 25%. Endocrine therapy clearly improves outcomes in patients with estrogen receptor-positive breast cancer. In the metastatic setting, the primary goal of treatment is to maintain long-term disease control with good quality of life. Rarely, exceptional responders achieve durable disease control, and potential cures cannot be ruled out. PATIENT CONCERNS: We report the case of a 39-year-old woman with primary breast cancer and associated synchronous bone metastases, who experienced a disease response of 12 years with hormonal therapy as maintenance after first line chemotherapy, with a good toxicity profile. DIAGNOSIS: The patient was diagnosed with estrogen receptor + human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer with synchronous bone metastases. INTERVENTIONS: This patient was treated with chemotherapy for 6 cycles as a first-line therapy following by endocrine treatment given as a maintenance therapy. OUTCOMES: Our patient experienced a progression-free survival >12 years with an exceptionally good quality of life. LESSONS: Our anecdotal experience highlights the existence of exceptional responders among patients with hormone receptor-positive metastatic breast cancer, who achieve clinical remission and durable disease control with endocrine therapy. Being able to identify these patients could help in the selection of the best treatment option among the many available

Evaluation of Androgen Receptor in Relation to Estrogen Receptor (AR/ER) and Progesterone Receptor (AR/PgR): A New Must in Breast Cancer?

Steroid nuclear receptors are known to be involved in the regulation of epithelial-mesenchymal transition process with important roles in invasion and metastasis initiation. Androgen receptor (AR) has been extensively studied, but its role in relation to breast cancer patient prognosis remains to be clarified. AR/ER ratio has been reported to be an unfavorable prognostic marker in early primary breast cancer, but its role in the patients with advanced disease has to be cleared. We retrospectively analyzed ER, PgR, and AR expression on a case series of 159 specimens of primary BC samples by using immunohistochemistry and 89 patients of these had luminal tumors for which AR and ER expression and survival data were available. For twenty-four patients both primary and metastatic tumors were available. A significantly shorter overall survival was observed in primary tumors with AR/PgR ratio 65 1.54 (HR = 2.27; 95% CI 1.30-3.97; p = 0.004). Similarly OS was significantly shorter when ER/PgR ratio 652 in primary tumors (HR = 1.89; 95% CI 1.10-3.24; p = 0.021). The analysis of the 24 patients who had biomarker determinations both in primary tumors and metastasis showed a better OS when AR/ER ratio in the metastasis was 65 0.90 (p = 0.022). Patients with a high AR/ER ratio in primary tumor that remained high in the metastasis had better prognosis in terms of OS (p = 0.011). Despite we suggested that the ratios AR/ER and AR/PgR could be used to identify patients with different prognosis, their real value needs to be better clarified in different BC settings through prospective studies

Assessment of DNA Damage and Telomerase Activity in Exfoliated Urinary Cells as Sensitive and Noninvasive Biomarkers for Early Diagnosis of Bladder Cancer in Ex-Workers of a Rubber Tyres Industry

The aim of the present study was to identify sensitive and noninvasive biomarkers of early carcinogenic effect at target organ to use in biomonitoring studies of workers at risk for previous occupational exposure to potential carcinogens. Standard urine cytology (Papanicolaou staining test), comet assay, and quantitative telomerase repeat amplification protocol (TRAP) assay were performed in 159 ex-rubber workers employed in tyres production and 97 unexposed subjects. In TRAP positive cases, a second level analysis using FISH (Urovysion) was done. Cystoscopy results were available for 11 individuals whose 6 FISH/TRAP/comet positive showed in 3 cases a dysplastic condition confirmed by biopsy, 1 comet positive resulted in infiltrating UBC to the biopsy and with hyperplasia and slight dysplasia to the urinary cytology, 1 comet positive resulted in papillary superficial UBC to the biopsy, 1 FISH/TRAP positive showed a normal condition, and 2 TRAP positive showed in one case a phlogosis condition. The results evidenced good concordance of TRAP, comet, and FISH assays as early biomarkers of procarcinogenic effect confirmed by the dysplastic condition and UBC found by cystoscopy-biopsy analysis. The analysis of these markers in urine cells could be potentially more accurate than conventional cytology in monitoring workers exposed to mixture of bladder potential carcinogens

Combining preclinical tools and models to unravel tumor complexity: Jump into the next dimension

Tumors are complex and heterogeneous diseases characterized by an intricate milieu and dynamically in connection with surrounding and distant tissues. In the last decades, great efforts have been made to develop novel preclinical models able to recapitulate the original features of tumors. However, the development of an in vitro functional and realistic tumor organ is still utopic and represents one of the major challenges to reproduce the architecture of the tumor ecosystem. A strategy to decrypt the whole picture and predict its behavior could be started from the validation of simplified biomimetic systems and then proceed with their integration. Variables such as the cellular and acellular composition of tumor microenvironment (TME) and its spatio-temporal distribution have to be considered in order to respect the dynamic evolution of the oncologic disease. In this perspective, we aim to explore the currently available strategies to improve and integrate in vitro and in vivo models, such as three-dimensional (3D) cultures, organoids, and zebrafish, in order to better understand the disease biology and improve the therapeutic approaches

The Interplay Between Programmed Death Ligand 1 and Vimentin in Advanced Non-Small-Cell Lung Cancer

none14noBackground: Current therapy for non-small-cell lung cancer (NSCLC) frequently includes immune checkpoint inhibitors, such as pembrolizumab, and programmed death ligand 1 (PD-L1) positivity is mandatory for its use in this setting. Vimentin plays a role in carcinogenesis through the activation of the epithelial-to-mesenchymal transition (EMT) process. Its prognostic impact in NSCLC has been investigated in numerous studies but little data are available on its relation with PD-L1 expression. Patients and Methods: We retrospectively retrieved data on patients with advanced NSCLC consecutively enrolled in a clinical trial at our institute. PD-L1 and vimentin expression were determined by immunohistochemistry. Correlations between variables were assessed using the Spearman correlation coefficient. The Kaplan-Meier method was used to estimate overall survival (OS) and the Log-rank test was used to compare survival curves. The association between demographic, clinical and biomarker information and survival was investigated with the Cox model. Results: Fifty-three patients were included in the study. A weak positive correlation was observed between the PD-L1 and vimentin (ρ=0.41, P=0.003). Patients with PD-L1 values <1% showed a slightly better OS than those with higher values (HR=2.07; 95% CI: 0.92–4.65), but the difference was not significant (P=0.080). No difference in overall survival (OS) was observed on the basis of vimentin expression (HR=1.25; 95% CI: 0.59–2.66; P=0.554). Patients harboring both vimentin and PD-L1 negative expression (<1%) showed a trend towards better survival than those with ≥1% expression (HR=2.31; 95% CI: 0.87-6.17, P=0.093). No significant associations were observed between gender, age at diagnosis, stage at diagnosis, histology, KRAS or EGFR status, radical surgery or immunotherapy and OS. Conclusions: The weak positive association between PD-L1 and vimentin suggests a potential interplay between these biomarkers. Further research is warranted to evaluate EMT and immune escape as two components of the same process.openBronte G.; Puccetti M.; Petracci E.; Landi L.; Cravero P.; Scodes S.; Ulivi P.; Ravaioli S.; Tumedei M.M.; Burgio M.A.; Cappuzzo F.; Delmonte A.; Crino L.; Bravaccini S.Bronte, G.; Puccetti, M.; Petracci, E.; Landi, L.; Cravero, P.; Scodes, S.; Ulivi, P.; Ravaioli, S.; Tumedei, M. M.; Burgio, M. A.; Cappuzzo, F.; Delmonte, A.; Crino, L.; Bravaccini, S

Androgen receptor in advanced breast cancer: Is it useful to predict the efficacy of anti-estrogen therapy?

none16noBackground: Androgen receptor (AR) is widely expressed in breast cancer (BC) but its role in estrogen receptor (ER)-positive tumors is still controversial. The AR/ER ratio has been reported to impact prognosis and response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced BC. Patients who had received first-line ET (2002-2011) were recruited, while those given concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy were excluded. ER, progesterone receptor (PgR), Ki67 and AR expression were assessed by immunohistochemistry, and HER2 mainly by fluorescent in-situ hybridization. Cut-offs of 1 and 10% immunostained cells were used to categorize AR expression. Results: Among 102 evaluable patients, biomarkers were assessed in primary tumors in 70 cases and in metastases in 49, with 17 patients having both determinations. The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR status. AR status did not affect TTP significantly, whereas PgR and Ki67 status did. AR/PgR ≥0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.028). AR status in primary tumors or metastases was not associated with progressive disease (PD) as best response. In contrast, Ki67 ≥ 20% and PgR < 10% showed a statistically significant association with PD as best response. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in advanced BC, whereas Ki67 and PgR exert a greater impact on its efficacy.openBronte G.; Rocca A.; Ravaioli S.; Puccetti M.; Tumedei M.M.; Scarpi E.; Andreis D.; Maltoni R.; Sarti S.; Cecconetto L.; Fedeli A.; Pietri E.; De Simone V.; Asioli S.; Amadori D.; Bravaccini S.Bronte, G.; Rocca, A.; Ravaioli, S.; Puccetti, M.; Tumedei, M. M.; Scarpi, E.; Andreis, D.; Maltoni, R.; Sarti, S.; Cecconetto, L.; Fedeli, A.; Pietri, E.; De Simone, V.; Asioli, S.; Amadori, D.; Bravaccini, S

T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer

The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers' choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago

The impact of progesterone receptor expression on prognosis of patients with rapidly proliferating, hormone receptor-positive early breast cancer: a post hoc analysis of the IBIS 3 trial

Background:In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status.Methods:RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available.Results:Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR 20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors.Conclusions:Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting