Null Mismatch Repair Proteins Expression Reveals the Temporal Molecular Events in Lynch Syndrome-Related Cancers.

The immunohistochemical assessment of mismatch repair (MMR) proteins represents a pivotal screening tool for identifying Lynch syndrome (LS)-related cancers, as the loss of their expression often indicates MMR dysfunction associated with genetic or epigenetic alterations. Frequently, LS-related colorectal cancers present germline pathogenic variants in the MLH1 or MSH2 genes, which result in the simultaneous immunohistochemical loss of MLH1 and PMS2 or MSH2 and MSH6 proteins expression, respectively. Less commonly observed is the single involvement of the MSH6 or PMS2 proteins expression, indicative of the presence of germline pathogenic variants in the corresponding genes. Extremely rarely reported are the null immunohistochemistry phenotypes represented by the complete loss of expression of all MMR proteins. The molecular mechanisms contributing to the raising of this latter uncommon immunohistochemical phenotype are derived from the combination of pathogenic germline variants in MMR genes with the somatic hypermethylation of the MLH1 gene promoter. This study focuses on elucidating the molecular cascade leading to the development of the null immunohistochemical phenotype, providing valuable insights into understanding the sequential molecular events driving the LS-associated tumorigenesis, which may have pivotal implications in the clinical management of patients with LS-related cancers.

Effect of L. crispatus M247 Administration on Pregnancy Outcomes in Women Undergoing IVF: A Controlled, Retrospective, Observational, and Open-Label Study.

The aim of our study was to retrospectively evaluate whether the oral administration of L. crispatus (M247) could increase pregnancy and live birth rates in women undergoing assisted reproductive technology procedures. Enrolled women (N = 160) were divided into two groups: treated (N = 80) or untreated (N = 80) with the probiotic strain. The odds ratio (OR) for a treated woman to have a clinical pregnancy (CP) was 1.56. In women aged 30-40 years, M247 increased the probability of a CP in correlation with the progressive rise in BMI, reaching 47% (35% in controls) with a BMI of 35 (OR: 2.00). The CAID statistics showed that in a woman of the blastocyst subgroup, below 43 years, with a BMI over 18.6, treatment with M247 increased the chance of a CP from 28.4% to 44.5% (OR: 2.08; p < 0.05). Considering live births, the rate of the probiotic group was 12.5% versus 7.5% (OR: 1.76). Considering only the blastocyst subgroup, the treatment increased the number of live births by 200% (OR: 3.64; p = 0.05). As confirmed also by statistical indices NNT, NNH, and LHH, the use of M247 demonstrated a risk-benefit ratio to the full advantage of the benefits.

Hereditary Cancer Syndromes: A Comprehensive Review with a Visual Tool.

Hereditary cancer syndromes account for nearly 10% of cancers even though they are often underdiagnosed. Finding a pathogenic gene variant could have dramatic implications in terms of pharmacologic treatments, tailored preventive programs, and familiar cascade testing. However, diagnosing a hereditary cancer syndrome could be challenging because of a lack of validated testing criteria or because of their suboptimal performance. In addition, many clinicians are not sufficiently well trained to identify and select patients that could benefit from a genetic test. Herein, we searched the available literature to comprehensively review and categorize hereditary cancer syndromes affecting adults with the aim of helping clinicians in their daily clinical practice through a visual tool.

Hypofractionated breast irradiation: a multidisciplinary review of the Senonetwork study group.

The multidisciplinary management represents a crucial part of the care for cancer patients, resulting in better clinical and process outcomes, with evidence of improved survival among different cancer primary sites, including breast. According with international recommendations established by the European Society of Breast Cancer Specialists (EUSOMA), all breast-cancer patients have to be evaluated by a multidisciplinary team including radiologist, pathologist, surgeon, medical oncologist and radiation oncologist. Thus, variations in clinical practice of each specialty should be discussed and shared with all team members to guarantee a fruitful cooperation among the involved specialists. During the last decades, radiation treatment was deeply changed by the evidence-based adoption of hypofractionated radiotherapy (HFRT) as standard of treatment in patients with early-stage breast cancer undergoing conservative surgery. Moreover, mature randomized data have showed that partial breast irradiation (PBI) is an effective and safe alternative to whole breast irradiation in selected patients with low-risk early-stage breast cancer. Based on this background, we reviewed indications and critical issues of HFRT and PBI analyzing impact of their adoption from a multidisciplinary perspective.

First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: A real-world study.

BACKGROUND: Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L. MATERIALS AND METHODS: 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated. RESULTS: At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi. CONCLUSION: Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines.

Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer.

BACKGROUND: Endocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25-30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment. METHODS: A cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann-Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test. RESULTS: The ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup. CONCLUSION: The study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity.

The SENECA study: Prognostic role of serum biomarkers in older patients with metastatic colorectal cancer.

BACKGROUND: Aging induces meaningful changes in the immune system and inflammation response with increase in monocyte-lymphocyte ratio (MLR) and serum lactate dehydrogenase (LDH) levels. Aim of this study was to explore the prognostic role of MLR and LDH levels in older patients (pts) with metastatic colorectal cancer (mCRC). METHODS: We conducted a retrospective analysis of a consecutive cohort of 168 older (>70 years) patients with mCRC. The prognostic impact of MLR and LDH levels on overall survival (OS) was investigated through uni-and multivariate Cox regression analyses. Moreover, we categorized patients into three groups according to MLR and LDH levels (group 1: MLR-low and LDH-low; group 2: MLR-high or LDH-high; group 3: MLR-high and LDH-high). RESULTS: By univariate analysis, high LDH level (HR 1.74, 95% CI 1.05-2.90) and high MLR level (HR 2.19, 95% CI 1.48-3.44) were significantly associated with a worse OS. Conversely, primary tumor resection and left-sidedness were significantly associated with a longer OS. By multivariate analysis, high LDH level (HR 2.00, 95% CI 1.13-3.55) and high MLR level (HR 2.99, 95% CI 1.68-5.33) were independent prognostic factors of worse prognosis. Compared to group 1, a shorter survival was reported for patients included in group 2 (HR 1.97, 95% CI 1.21-3.23 in univariate; HR 2.54, 95% CI 1.43-4.51 in multivariate) or in group 3 (HR 2.42, 95% CI 24-4.74, p = .010 in univariate; HR 5.59, 95% CI 2.15-14.54 in multivariate) CONCLUSIONS: High baseline levels of LDH, MLR or both are independent unfavorable prognostic factors in older patients treated with first-line chemotherapy for mCRC.

Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside.

Mucositis is one of the most common debilitating side effects related to chemotherapy (CT), radiation therapy (RT), targeted agents and immunotherapy. It is a complex process potentially involving any portion of the gastrointestinal tract and injuring the mucosa, leading to inflammatory or ulcerative lesions. Mechanisms and clinical presentation can differ according both to the anatomic site involved (oral or gastrointestinal) and the treatment received. Understanding the pathophysiology and management of mucosal injury as a secondary effect of anti-cancer treatment is an important area of clinical research. Prophylaxis, early diagnosis, and adequate management of complications are essential to increase therapeutic success and, thus, improve the survival outcomes of cancer patients. This review focuses on the pathobiology and management guidelines for mucositis, a secondary effect of old and new anti-cancer treatments, highlighting recent advances in prevention and discussing future research options.

HER2-Positive Lobular Versus Ductal Carcinoma of the Breast: Pattern of First Recurrence and Molecular Insights.

BACKGROUND: Infiltrating lobular carcinoma (ILC) represents about 10% of breast cancer and rarely shows overexpression of human epidermal growth factor receptor 2 (HER2). We compared biological and clinical characteristics of HER2-positive ILC versus HER2-positive infiltrating ductal carcinoma (IDC). PATIENTS AND METHODS: We retrospectively analyzed the data of 328 patients with HER2-positive pure ductal or lobular breast carcinoma, comparing clinical and biological data at diagnosis as well as outcome between the 2 histologies. A gene-mutation analysis was performed in a subset of patients. RESULTS: Two hundred ninety-one patients (88.7%) had IDC and 37 patients (11.3%) ILC. ILC resulted more frequently in multicenter (24.3% vs. 6.5%, P < .0001) and node-positive (54.1% vs. 45%, P = .013) disease of lower proliferative activity (Mib1 < 20%: 51.4% vs. 22.3%, P < .0001) and lower histologic grade (grade 3: 32.4% vs. 57.4%, P = .038). Disease recurred in 57 patients (17.4%) and involved the bone in 40% of ILC patients (vs. 17% of IDC patients) and the viscera in 30% of ILC patients (vs. 59.6% of IDC patients). No difference in the recurrence rate between the 2 histologies was observed in patients treated with adjuvant trastuzumab (12.5% of ILC patients and 8.3% of IDC patients). Exploratory molecular analysis revealed a higher frequency of mutations in ILC, with more cases of multiple mutations. CONCLUSION: HER2-positive ILC shows different biological behavior than IDC, with a possible higher mutation load. Despite lower proliferation activity and estrogen receptor expression in ILC breast cancer, trastuzumab is clearly an effective therapy for this histologic subtype.

"Triple positive" early breast cancer: an observational multicenter retrospective analysis of outcome.

We recently found that trastuzumab benefit may be lower in a small subset of early breast cancer (BC) patients (pts) with tumors expressing high levels of both hormonal receptors (HRs), i.e. triple positive (TP). To better investigate the role of HRs in HER2 positive BC, we retrospectively identified 872 TP BC pts treated with adjuvant chemotherapy alone (cohort A-366 pts), or plus trastuzumab (cohort B-506 pts). Relapse-free-survival (RFS) and breast-cancer-specific-survival (BCSS) were evaluated. Trastuzumab improved RFS and BCSS in all the subsets analyzed, but the effect on BCSS in tumors expressing both HRs in >30% of cells (TP30), and even on RFS in tumors with both HRs expressed in >50% of cells (TP50) was not significant. Distinct patterns of relapse were observed in TP50 and no-TP50 tumors, the former showing low and constant risk in the first 5 years, a late increase beyond 5 years and modest trastuzumab effect. Trastuzumab effect tended to disappear in pts whose tumors expressed ER in >50% of cells. Multivariate analysis of RFS confirmed a significant interaction between trastuzumab and ER expression, with benefit confined to pts whose tumors expressed ER in ≤50% of cells. Our data suggest that the pattern of relapse of TP tumors with high HRs is similar to that of "luminal", HER2 negative tumors, without clear benefit from adjuvant trastuzumab, which remains the standard treatment even in TP tumors. Confirmatory findings on the extent to which quantitative expression of HRs may impact clinical behavior of HER2 positive BC are warranted.

Reversibility of Left Ventricle Longitudinal Strain Alterations Induced by Adjuvant Therapy in Early Breast Cancer Patients.

Left ventricular ejection fraction (LV-EF), despite its high feasibility, is not sensitive enough to detect early and subtle LV systolic dysfunction during oncologic treatments. Therefore, we used systolic global longitudinal strain (GLS) by speckle tracking echocardiography to verify whether early LV systolic dysfunction induced by adjuvant therapy in early breast cancer patients at low risk for cardiotoxicity can be reversed. Thirty patients (aged 53 ± 11 y) with no previous cardiac and oncologic disease who were receiving adjuvant trastuzumab and taxane (group HER2+, n = 15) or taxane only (group HER2-, n = 15), after treatment with anthracyclines, were studied. LV-EF and GLS were measured at baseline, after anthracyclines (end of week 7 or 8), short term after trastuzumab and/or taxane (end of week 18) and after completion of therapy. Significant LV systolic dysfunction was defined as a relative reduction in GLS of >10% with respect to baseline values. Mean and individual LV-EFs did not change significantly during the oncologic treatment and after completion of therapy, although GLS varied significantly. In particular, during the course of therapy, four patients in the trastuzumab-docetaxel HER2+ subgroup and two patients in the taxane HER2- subgroup had a relative decrease (>10%) in GLS. However, after the end of adjuvant treatment, strain modification was fully or partially reversible. Speckle tracking echocardiography is more sensitive than LV-EF in recognizing subtle myocardial impairment during adjuvant chemotherapy. However, in patients at low risk for cardiotoxicity, these alterations may be reversible and not associated with clinically significant cardiotoxicity or late development of decreased LV-EF.

Absolute quantification of cell-free microRNAs in cancer patients.

The hypothesis to use microRNAs (miRNAs) circulating in the blood as cancer biomarkers was formulated some years ago based on promising initial results. After some exciting discoveries, however, it became evident that the accurate quantification of cell-free miRNAs was more challenging than expected. Difficulties were linked to the strong impact that many, if not all, pre- and post- analytical variables have on the final results. In this study, we used currently available high-throughput technologies to identify miRNAs present in plasma and serum of patients with breast, colorectal, lung, thyroid and melanoma tumors, and healthy controls. Then, we assessed the absolute level of nine different miRNAs (miR-320a, miR-21-5p, miR-378a-3p, miR-181a-5p, miR-3156-5p, miR-2110, miR-125a-5p, miR-425-5p, miR-766-3p) in 207 samples from healthy controls and cancer patients using droplet digital PCR (ddPCR) technology. We identified miRNAs specifically modulated in one or more cancer types, according to tissue source. The significant reduction of miR-181a-5p levels in breast cancer patients serum was further validated using two independent cohorts, one from Italy (n = 70) and one from US (n = 90), with AUC 0.66 and 0.73 respectively. This study finally powers the use of cell-free miRNAs as cancer biomarkers and propose miR-181a-5p as a diagnostic breast cancer biomarker.