PARP Inhibitors for Breast Cancer Treatment: A Review.

Importance: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients. Observations: This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies. Conclusions and Relevance: Although the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.

Evaluation of the Geographical Accessibility of Genome-Matched Clinical Trials on a National Experience.

BACKGROUND: Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. MATERIAL AND METHODS: We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. RESULTS: We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. CONCLUSIONS: The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer.

Immune-Related Adverse Event Likelihood Score Identifies "Pure" IRAEs Strongly Associated With Outcome in a Phase I-II Trial Population.

BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the "post-CDK4/6is" landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario.

NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential.

Introduction: Constitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL. Methods: We performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eµ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling. Results and discussion: Bioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eµ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL.

Therapeutic Targeting Potential of Novel Silver Nanoparticles Coated with Anti-CD20 Antibody against Chronic Lymphocytic Leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored. METHODS: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy. RESULTS: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent. CONCLUSIONS: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs' non-specific distribution and increasing their efficacy.

Impact of soluble tumor necrosis factor-related apoptosis-inducing ligand released by engineered adipose mesenchymal stromal cells on white blood cells.

BACKGROUND AIMS: The proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer. However, the impact of AD-MSC sTRAIL on leukocyte subsets has been not yet considered also to predict a possible immunotoxicity profile in the clinical translation of this cell-based anticancer strategy. METHODS: Monocytes, polymorphonuclear cells and T lymphocytes were freshly isolated from the peripheral blood of healthy donors. Immunophenotype and functional (DR4 and DR5) and decoy (DcR1 and DcR2) TRAIL receptors were tested by flow cytometry. The viability of white blood cells treated with sTRAIL released by gene-modified AD-MSC or co-cultured with AD-MSC sTRAIL was then evaluated by both metabolic assays and flow cytometry. In addition, cytokine profile in co-cultures was analyzed by multiplex enzyme-linked immunosorbent assay. RESULTS: Monocytes and polymorphonuclear cells showed high positivity for DR5 and DcR2, respectively, whereas T cells revealed negligible expression of all TRAIL receptors. Irrespective of TRAIL receptors' presence on the cell membrane, white blood cells were refractory to the proapoptotic effect displayed by sTRAIL secreted by gene-modified AD-MSC, and direct cell-to-cell contact with AD-MSC sTRAIL had negligible impact on T-cell and monocyte viability. Cytokine crosstalk involving interleukin 10, tumor necrosis factor alpha, and interferon gamma secreted by T lymphocytes and vascular endothelial growth factor A and interleukin 6 released by AD-MSC was highlighted in T-cell and AD-MSC sTRAIL co-cultures. CONCLUSIONS: In summary, this study demonstrates the immunological safety and thus the clinical feasibility of an anticancer approach based on AD-MSC expressing the proapoptotic molecule sTRAIL.

Evolution of biological features of invasive lobular breast cancer: Comparison between primary tumour and metastases.

BACKGROUND: Invasive lobular carcinoma (ILC) has unique clinical-biological features. Phenotypical differences between primary tumours (PTs) and metastases (M) have been described for invasive ductal carcinoma, but data on ILC are limited. METHODS: We retrospectively analysed patients with recurrent ILC from our institution from 2013 to 2020. We evaluated the discordance of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2 between PT and M, to understand prognostic and therapeutic implications. RESULTS: Thirteen percent (n = 91) of all patients had ILC. We observed 15%, 44% and 5% of ER, PgR and HER2 status discordance between PT and M. ER/PgR discordance was related to receptor loss and HER2 mainly due to gain. PT presented a luminal-like phenotype (93%); 6% and 1% were triple-negative (TNBC) and HER2-positive. In M, there was an increase in TNBC (16%) and HER2-positive (5%). Metastasis-free survival and overall survival (OS) were different according to clinical phenotype, with poorer prognosis for HER2+ and TNBC (p < 0.001); OS after metastatic progression did not differ across phenotypes (p = 0.079). In luminal-like ILC (n = 85) at diagnosis, we found that OS after relapse was poorer in patients experiencing a phenotype switch to TNBC but improved in patients with HER2 gain (p = 0.0028). Poorer survival was reported in patients with a PgR and/or ER expression loss of ≥25%. There was HER2-low enrichment in M1 (from 37% to 58%): this change was not associated with OS (p > 0.05). CONCLUSION: Our results suggest that phenotype switch after metastatic progression may be associated with patients' outcomes. Tumour biopsy in recurrent ILC could drive treatment decision-making, with prognostic implications.

Molecular tumour board at European Institute of Oncology: Report of the first three year activity of an Italian precision oncology experience.

BACKGROUND: Precision oncology aims to improve clinical outcomes by personalising treatment options for patients with cancer. Exploiting vulnerabilities identified in a patient's cancer genome requires reliable interpretation of a huge mole of alterations and heterogeneous biomarkers. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) allows evidence-based evaluation of genomic findings. Molecular tumour boards (MTBs) convey the required multi-disciplinary expertise to enable ESCAT evaluation and strategical treatment choice. MATERIALS AND METHOD: We retrospectively reviewed the records of 251 consecutive patients discussed by European Institute of Oncology MTB between June 2019 and June 2022. RESULTS: One-hundred eighty-eight (74.6%) patients had at least one actionable alteration. After MTB discussion, 76 patients received molecularly matched therapies (MMTs) while 76 patients received standard of care. Patients receiving MMT displayed higher overall response rate (37.3% versus 12.9%), median progression-free survival (mPFS 5.8 months, 95% confidence interval [CI] 4.1-7.5 versus 3.6 months, 95% CI 2.5-4.8, p = 0.041; hazard ratio 0.679, 95% CI 0.467-0.987) and median overall survival (mOS 35.1 months, 95% CI not evaluable versus 8.5 months, 95% CI 3.8-13.2; hazard ratio 0.431, 95% CI 0.250-0.744, p = 0.002). Superiority in OS and PFS persisted in multivariable models. Among 61 pretreated patients receiving MMT, 37.5% of patients had PFS2/PFS1 ratio ≥1.3. Patients with higher actionable targets (ESCAT tier I) had better OS (p = 0.001) and PFS (p = 0.049), while no difference was observed in lower evidence levels. CONCLUSIONS: Our experience shows that MTBs can yield valuable clinical benefit. Higher actionability ESCAT level appears to be associated with better outcomes for patients receiving MMT.

Immune correlates of protection by vaccine against SARS-CoV-2 in patients with chronic lymphocytic leukaemia.

In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion was observed in 55.2% of CLL with lower rate and antibody titres in treated patients. T-cell responses were detected in a significant fraction of patients. CD4+ and CD8+ frequencies were significantly increased independent of serology with higher levels of CD4+ cells in patients under a Bruton tyrosine kinase (BTK) or a B-cell lymphoma 2 (BCL-2) inhibitor. Vaccination skewed CD8+ cells towards a highly cytotoxic phenotype, more pronounced in seroconverted patients. A high proportion of patients showed spike-specific CD4+ and CD8+ cells producing interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). Patients under a BTK inhibitor showed increased production of IFNγ and TNFα by CD4+ cells. Vaccination induced a Th1 polarization reverting the Th2 CLL T-cell profile in the majority of patients with lower IL-4 production in untreated and BTK-inhibitor-treated patients. Such robust T-cell responses may have contributed to remarkable protection against hospitalization and death in a cohort of 540 patients. Combining T-cell metrics with seroprevalence may yield a more accurate measure of population immunity in CLL, providing consequential insights for public health.

An Extremely Rare Case of Disseminated Peritoneal Leiomyomatosis with a Pelvic Leiomyosarcoma and Omental Metastasis after Laparoscopic Morcellation: Systematic Review of the Literature.

Minimally invasive treatment of uterine fibroids usually requires a power morcellation, which could be associated with several complications. A rare sequela is disseminated peritoneal leiomyomatosis. Indeed, recurrence or metastasis in these cases could be attributed to iatrogenic or under-evaluation of primary tumors, although a subset of cases is a sporadic sample of biological progression. We present an extremely rare case of a patient who underwent laparoscopic morcellation and after 12 years developed a pelvic leiomyosarcoma with two omental metastases, disseminated peritoneal leiomyomatosis with a parasite leiomyoma with bizarre nuclei and a parasite cellular leiomyoma simultaneously. The diagnosis was predicted preoperatively by an expert sonographer who recognized the ultrasound characteristics of uterine sarcoma and the localization of some of the masses, so the patient was referred to the gynaecological oncologists who could appropriately treat her. We present here a case report and a systematic review that could be a useful tool for further discussion and future clinical practice guidelines.

GSK3ß is a critical, druggable component of the network regulating the active NOTCH1 protein and cell viability in CLL.

NOTCH1 alterations have been associated with chronic lymphocytic leukemia (CLL), but the molecular mechanisms underlying NOTCH1 activation in CLL cells are not completely understood. Here, we show that GSK3ß downregulates the constitutive levels of the active NOTCH1 intracellular domain (N1-ICD) in CLL cells. Indeed, GSK3ß silencing by small interfering RNA increases N1-ICD levels, whereas expression of an active GSK3ß mutant reduces them. Additionally, the GSK3ß inhibitor SB216763 enhances N1-ICD stability at a concentration at which it also increases CLL cell viability. We also show that N1-ICD is physically associated with GSK3ß in CLL cells. SB216763 reduces GSK3ß/N1-ICD interactions and the levels of ubiquitinated N1-ICD, indicating a reduction in N1-ICD proteasomal degradation when GSK3ß is less active. We then modulated the activity of two upstream regulators of GSK3ß and examined the impact on N1-ICD levels and CLL cell viability. Specifically, we inhibited AKT that is a negative regulator of GSK3ß and is constitutively active in CLL cells. Furthermore, we activated the protein phosphatase 2 A (PP2A) that is a positive regulator of GSK3ß, and has an impaired activity in CLL. Results show that either AKT inhibition or PP2A activation reduce N1-ICD expression and CLL cell viability in vitro, through mechanisms mediated by GSK3ß activity. Notably, for PP2A activation, we used the highly specific activator DT-061, that also reduces leukemic burden in peripheral blood, spleen and bone marrow in the Eµ-TCL1 adoptive transfer model of CLL, with a concomitant decrease in N1-ICD expression. Overall, we identify in GSK3ß a key component of the network regulating N1-ICD stability in CLL, and in AKT and PP2A new druggable targets for disrupting NOTCH1 signaling with therapeutic potential.

Evolution of low HER2 expression between early and advanced-stage breast cancer.

BACKGROUND: Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. METHODS: We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. RESULTS: 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21-0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19-0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. CONCLUSIONS: HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression.

Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials.

Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.

Clinical outcomes of patients with metastatic breast cancer enrolled in phase I clinical trials.

BACKGROUND: Next-generation phase I clinical trials (Ph1s) investigating targeted therapy (TT) and immunotherapy (IO) led to consistent improvements in outcomes of patients with cancer . Ph1s are mainly designed to enrol patients with different tumour types; hence, scant information on characteristics and outcomes of specific tumours is available. The aim of our study is to evaluate the outcomes of patients with metastatic breast cancer (BC) enrolled in Phs1 testing TT, IO and combinations. MATERIAL AND METHODS: We retrospectively collected data on clinical characteristics and outcomes of all patients with metastatic BC treated in Ph1s from 2014 to 2019 at our Institution. The primary end-points were progression-free survival (PFS) and overall survival (OS). The secondary objectives were overall response rate (ORR), disease control rate (DCR) and 90-day mortality rate. Univariate and multivariate analyses were performed to assess the impact of different variables. RESULTS: One hundred fifty-one patients with metastatic BC were treated, including 70 (46%) with hormone receptor-positive (HR+), 18 (12%) with HER2+ and 63 (42%) with triple-negative (TN) BC. The median age was 52.4 years (26.9-77.9). Patients with TNBC were less pretreated than patients with HR+ and HER2+ subtypes. Patients with HR+ tumours were preferentially included in TT rather than IO trials (97% vs. 2.9%, P < 0.001). In 148 patients evaluable for tumour response, DCR and ORR were 51.4% and 18.9%, respectively. Higher response rates have been observed in patients treated with TT (TT vs. IO: 23.5% vs. 3.0%, P = 0.008) and in the HER2+ or TN subtypes (HER2+ vs. TN vs. HR+: 33.3% vs. 24.2% vs. 10.3%, P = 0.032). Improved median PFS was observed in patients treated with TT (P < 0.001), aged ≥ 65 years (P = 0.001) and having fewer than 3 metastatic sites (P = 0.026). Patients with HR+ and HER2+ subtypes presented a numerically higher median PFS than those with TNBC (3.65 vs. 3.58 vs. 2.28 months, P = 0.053). Median OS was longer in HR+ and HER2+ subtypes than that in TNBC (20 vs. 16 vs. 10 months, P = 0.007). Variables independently associated with improved OS were fewer than three metastatic sites (P = 0.014) and a baseline lactate dehydrogenase lower than upper limit of normal (P < 0.001). CONCLUSION: Our study provides novel insights on the landscape of metastatic breast cancer metasta treated in Ph1s. Patients with TNBC still have poor outcomes, reinforcing the need to better translate preclinical findings into the clinical context. TT-based trials-mainly biomarker-driven-are associated with improved outcomes, suggesting that future IO trials have to be guided by meaningful biomarkers. Finally, patients with low tumour burden can have significant benefit, underling the importance to enrol patients in earlier lines of treatment to maximise the benefit.

Body mass index, adiposity and tumour infiltrating lymphocytes as prognostic biomarkers in patients treated with immunotherapy: A multi-parametric analysis.

BACKGROUND: We performed a multi-parametric analysis investigating the association between adiposity (as measured using body mass index [BMI] and computed tomography [CT]-based body composition), tumour infiltrating lymphocytes (TILs) and clinical outcomes in patients with advanced-stage cancer treated with immunotherapy in phase I clinical trials. MATERIAL AND METHODS: All consecutive patients (N = 153) with metastatic solid tumours treated within immunotherapy-based phase I clinical trials between August 2014 and May 2019 at our institution were included. Baseline characteristics, BMI, TILs value and CT-assessed fat indices (total fat area [TFA], subcutaneous fat area [SFA] and visceral fat [VFA]) were collected. The primary endpoints were to evaluate the impact of these parameters on overall survival (OS) and progression-free survival (PFS). Kaplan-Meier method and Cox proportional-hazards model were used for survival analyses. RESULTS: At both univariate and multivariate analyses, BMI was not associated with PFS neither when considered as continuous variable (HR 0.90, 95% CI 0.74-1.09, P = 0.28) nor as dichotomous variable (underweight/normal versus overweight/obese) (HR 0.79, 95% CI 0.55-1.14, P = 0.21). Interestingly, patients diagnosed with 'immunogenic' tumours and higher VFA/SFA ratio (1st and 2nd tertile versus 3rd tertile) presented an increased OS (HR 0.88, 95% CI 0.78-1.00, P = 0.047). CONCLUSION: Our analysis showed that patients with tumours that are already known as responsive to ICIs with higher VFA/SFA ratio presented an increased OS. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.

Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials.

BACKGROUND: Peripheral blood parameters are correlated to immune-checkpoint inhibitor efficacy in solid tumors, such as melanoma and non-small cell lung cancer. Few data are currently available on the prognostic role of these immune-inflammatory biomarkers for other solid tumors and immunotherapy combinations. MATERIAL AND METHODS: From August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression-free survival (PFS) and overall survival (OS). RESULTS: The most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil-to-lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.30-2.99; p = .001, and HR, 2.29; 95% CI, 1.39-3.77; p = .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26-3.28; p = .004, and HR, 2.06; 95% CI, 1.12-3.79; p = .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at "good" (dNLR <3 and LDH < upper limit of normal [ULN]) and "intermediate and poor" (dNLR >3 and/or LDH > ULN) risk had higher and lower PFS, respectively (p for interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (p for interaction = .004). CONCLUSION: Elevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy-based clinical trials. IMPLICATIONS FOR PRACTICE: In this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil-to-lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low-cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response.

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response.

Pharmacological management of male breast cancer.

INTRODUCTION: Despite its rarity, male breast cancer shows a steadily rising incidence. Given the absence of ad hoc prospective randomized clinical trials, treatment strategies are based on extrapolation from female breast cancer recommendations or solely on population-based data. AREAS COVERED: This review discusses the current treatment landscape for male breast cancer in the adjuvant and in the metastatic setting. The authors also discuss the biology and genomic landscape of male breast cancer. Original research and review articles, relative to the period 2010-2019, were included in the review of the literature. EXPERT OPINION: There is a major medical need to include male patients with breast cancer in prospective clinical trials. The call to equality in breast cancer care can be pursued via two divergent paths: (i) a gender-neutral delivery of breast cancer information and (ii) the creation of separate sections, for the more common female breast cancer and for the rare male ones. We propose to differentiate male breast cancer care, acknowledging unique onco-sexual and social needs that can be only partially shared.