Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients' (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN). METHODS: PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test. RESULTS: Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum-maximum 1-23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723. CONCLUSIONS: Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02864030.

Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients.

Exploring treatment with Ribociclib alone or in sequence/combination with Everolimus in ER+HER2-Rb wild-type and knock-down in breast cancer cell lines.

BACKGROUND: Breast cancer (BC) is the second most common type of cancer worldwide. Among targeted therapies for Hormone Receptor-positive (HR+) and Human Epidermal growth factor Receptor 2-negative (HER2-) BC, the Cyclin-Dependent Kinases (CDK4/6) are targeted by inhibitors such as Ribociclib (Rib); however, resistance to CDK4/6 inhibitors frequently develops. The aim of this work is to assess in vitro activity of Rib and Everolimus (Eve) in HR+HER2- MCF-7 and HR-HER2-BT-549 BC cell lines. METHODS: HR+HER2- MCF-7 and HR-HER2- BT-549 BC cell lines were treated with increasing concentration of Rib and Eve (up to 80 µg/mL) for 48-72 h. Subsequently, HR+HER2- MCF-7 cells were silenced for Retinoblastoma (Rb) gene, and thus, the effect of Rib in sequential or concurrent schedule with Eve for the treatment of both Rb wild type or Rb knock-down MCF-7 in vitro was evaluated. Cell viability of HR+HER2- MCF-7cells treated with sequential and concurrent dosing schedule was analyzed by MTT assay. Moreover, cell cycle phases, cell death and senescence were evaluated by cytofluorimetric analysis after treatment with Rib or Eve alone or in combination. RESULTS: The sequential treatment didn't produce a significant increase of cytotoxicity, compared to Rib alone. Instead, the cotreatment synergized to increase the cytotoxicity compared to Rib alone. The cotreatment reduced the percentage of cells in S and G2/M phases and induced apoptosis. Rib triggered senescence and Eve completely reversed this effect in Rb wild type BC cells. Rib also showed Rb-independent effects as shown by results in Rb knock-down MCF-7. CONCLUSION: Overall, the Rib/Eve concurrent therapy augmented the in vitro cytotoxic effect, compared to Rib/Eve sequential therapy or single treatments.

Effects of Eribulin on the RNA Content of Extracellular Vesicles Released by Metastatic Breast Cancer Cells.

Extracellular vesicles (EVs) are small lipid particles secreted by almost all human cells into the extracellular space. They perform the essential function of cell-to-cell communication, and their role in promoting breast cancer progression has been well demonstrated. It is known that EVs released by triple-negative and highly aggressive MDA-MB-231 breast cancer cells treated with paclitaxel, a microtubule-targeting agent (MTA), promoted chemoresistance in EV-recipient cells. Here, we studied the RNA content of EVs produced by the same MDA-MB-231 breast cancer cells treated with another MTA, eribulin mesylate. In particular, we analyzed the expression of different RNA species, including mRNAs, lncRNAs, miRNAs, snoRNAs, piRNAs and tRNA fragments by RNA-seq. Then, we performed differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and miRNA-target identification. Our findings demonstrate the possible involvement of EVs from eribulin-treated cells in the spread of chemoresistance, prompting the design of strategies that selectively target tumor EVs.

Clinical Outcomes of HER2-Negative Metastatic Breast Cancer Patients in Italy in the Last Decade: Results of the GIM 13-AMBRA Study.

GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes-based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79-19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months-95% CI 5.7-9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7-15.1) and Luminal B patients (11.8 months, 95% CI 10.3-12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3-6.5 vs. Luminal A-9.4, 95% CI 8.1-10.7, and Luminal B-7.7 95% CI 6.8-8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8-37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2-31.2) and TNBC (18.5 months, 95% CI 16-20.1, F-ratio 7.44, p = 0.0006). The GIM 13-AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients.

Ribociclib Plus Letrozole in Italian Male Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Case Studies of Phase 3b CompLEEment-1 Trial.

Abstract: Male breast cancer (BC) is rare, globally constituting only 0.5-1% of all patients with BC. In Italy, more than 2000 new male BC cases were registered between 2000 and 2014. The survival rate was lower in males than in females. Delayed diagnosis may be the reason for poorer outcome observed in male BC patients compared with female patients. Due to lack of substantial evidence and low availability of published data on male BC, the current treatment recommendations are based on evidence derived from trials on female patients. In Italy, most of the male BC patients are estrogen and progesterone receptor-positive. Targeted therapy in combination with endocrine therapy provides a clinically meaningful outcome in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced BC. CompLEEment-1 is a single-arm, open-label, multicenter, phase 3b trial investigating the safety and efficacy of a CDK4/6 inhibitor, ribociclib, in combination with letrozole in men and women. Herein, we report the results from a retrospective analysis of five Italian male patients who completed the core phase. In this case series, the combination of ribociclib and letrozole was well tolerated and appeared to be effective in the male cohort with HR-positive, HER2-negative advanced BC in Italy. CompLEEment-1 trial representative of a real-world setting would add value by supporting the existing efficacy and safety profile of ribociclib in combination with letrozole in male patients with HR-positive, HER2-negative advanced BC. ClinicalTrialsgov Registration Number: NCT02941926.

Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications.

About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors. A positive feedback loop links mTOR and ER that support each other. We subsequently considered whether a combined or sequential inhibition of CDK4/6 and PI3K/AKT/mTOR could ensure better results. Studies indicate that inhibition of CDK4/6 activates mTOR as an escape mechanism to ensure cell proliferation. In literature, the little evidence dealing with this topic suggests that pre-treatment with mTOR pathway inhibitors could prevent or delay the onset of CDK4/6 inhibitor resistance. Additional studies are needed in order to find biomarkers that can identify patients who will develop this resistance and in whom the sensitivity to CDK4/6 inhibitors can be restored.

Is There Still a Role for Endocrine Therapy Alone in HR+/HER2- Advanced Breast Cancer Patients? Results from the Analysis of Two Data Sets of Patients Treated with High-Dose Fulvestrant as First-Line Therapy in the Real-World Setting: The EVA and GIM-13 AMBRA Studies.

BACKGROUND: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting. METHODS: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies). RESULTS: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35-82) for the EVA and 57.8 years (range 35.0-82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1-48) and 12.4 months (range 2.9-70.0) in the two data sets, respectively. CONCLUSION: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

Different Cardiotoxicity of Palbociclib and Ribociclib in Breast Cancer: Gene Expression and Pharmacological Data Analyses, Biological Basis, and Therapeutic Implications.

Breast cancer is the most frequent tumor in women. The recent advent of cyclin-dependent kinase (CDK) 4/6 inhibitors palbociclib and ribociclib has represented a major step forward for patients with hormone receptor-positive breast cancer. These two agents have showed similar efficacy in terms of breast cancer outcome but different cardiotoxic effects. In particular, ribociclib, but not palbociclib, has been associated with QT interval prolongation, and the mechanisms underlying this event are still unclear. In order to clarify such difference, we matched the candidate genes associated with QT interval prolongation with genes whose expression is altered following palbociclib or ribociclib treatment. We also investigated whether pharmacokinetic and pharmacodynamic characteristics, such as IC50 (hERG) [concentration of drug producing 50% inhibition (human ether-à-go-go related gene)] and maximum concentration (Cmax), could justify the different effects on QT interval prolongation. Our results show that ribociclib, but not palbociclib, could act by down-regulating the expression of KCNH2 (encoding for potassium channel hERG) and up-regulating SCN5A and SNTA1 (encoding for sodium channels Nav1.5 and syntrophin-α1, respectively), three genes associated with long QT syndrome. Consistent with the cardiotoxicity induced by ribociclib, its IC50 (hERG)/free concentration (Cmax free) ratio is closer to the safety threshold than that of palbociclib. In summary, we hypothesize that the different cardiotoxicity associated with ribociclib and palbociclib could be due to the alteration of potassium and sodium channels induced by ribociclib. A better comprehension of the mechanisms of cardiac channelopathies and drug-induced QT interval prolongation will be fundamental to avoid serious and potentially lethal adverse events and, as a consequence, optimize the management of breast cancer patients.

Gastric cancer treatment: a systematic review.

Gastric cancer remains one of the leading causes of cancer related deaths worldwide. The overall 5-year survival rate in the United States and most of the Western World ranges from 5 to 15%. The only potentially curative treatment for localized gastric cancer is complete surgical resection. Meta-analyses of adjuvant systemic chemotherapy in gastric cancer have shown at best marginal benefits, neoadjuvant chemotherapy and chemoradiotherapy are also feasible and are the subject of several ongoing studies. In metastatic disease, chemotherapy confers benefit when compared with best supportive care alone. This review will focus on the several treatment modalities available for gastric cancer patients: surgery, adjuvant, neoadjuvant and palliative chemotherapy as well as new target agents.

Compliance with breast and cervical cancer screening programs in women: results from a population-based study.

AIMS AND BACKGROUND: Women's adherence to mammography and PAP test screening guidelines is a fundamental topic regarding women's health. The aim of the study was to evaluate the knowledge and compliance to breast and cervical cancer screening programs in women living in three Italian towns, where a public screening program, consisting of free mammography every two years and free PAP test every three years, is ongoing. METHODS: An anonymous survey was mailed to a random sample of women. Eight 120-min focus discussions with groups of women exploring perceptions, knowledge and practices were carried out after analysis of the returned surveys. RESULTS: Replies were received from 1345 women (response rate, 27%). Almost every woman knew of the screening program, but women's practice of mammography was age-dependent: up to 72% of the women performed it before the age of 50. Conversely, the age of the first PAP test was rather late: up to 70% of the women performed it at over 30 years of age. Women with a lower educational level reported being screened less than those with a higher level. During the group discussions, women's perceptions, knowledge and beliefs regarding cancer and screening, together with aspects of the health care system, appeared to strongly influence the preventive practices. Many women deplored being infrequently instructed by health professionals. CONCLUSIONS: Despite the limitations of the study due to the low response rate, we believe that health professionals should invest on encouraging factors and reduce the deterring factors to optimize screening practices.