Frequency of Deleterious Germline Variants in HER2-Low Breast Cancer Patients Using a Hereditary Multipanel Gene Testing.

HER2-Low is defined as low levels of HER2 expression, based on a score of 1+ on immunohistochemical (IHC) assay or as an IHC score of 2+ and negative results on in situ hybridization (ISH or FISH). They are a heterogeneous population of breast cancers that vary in prognosis and sensitivity to systemic treatments. The frequency and clinical characteristics of pathogenic germline variants (PGVs) in HER2-Low breast cancer (BC) patients is not defined. We analyzed results from patients with BC who underwent multi-gene panel testing (MGPT) (maximum 145 genes) between 2018-2019. We reclassified HER-2 status accordingly. Relationships between the variables of interest were assessed by adopting the proportional regression Cox models. Of a total of 167 BC patients who underwent MGPT, half were hormone-receptor-positive. The median age was 45 years. About two thirds of the patients were in the earlier stage of BC. A total of 57% of the cases were reclassified as HER-2-negative or -Low. PGVs were found in 19% of the patients overall, as follows: seven BRCA1, four BRCA2, two ATM, one ATR, two CFTR, three CHEK2, one FANCA, one MERTK, one MLH1, three MUTYH, one RAD50, three RAD51C, one RECQL4, and two TP53 mutations. In HER2-Low, 26.5% of the patients had PGVs, and in the overall cohort, this was 19.8%. In conclusion, differences in the prevalence of deleterious germline mutations in HER2-Low BC patients compared to non-HER2-Low BC patients were identified. Similar alterations in BRCA were observed in this group of patients compared to the overall cohort. Germline genetic tests should be evaluated in larger cohorts of patients with HER2-Low status to better address the findings.

PARP inhibitors in non-ovarian gynecologic cancers.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the treatment of ovarian cancer, particularly benefiting patients whose tumors harbor genomic events that result in impaired homologous recombination (HR) repair. The use of PARPi over recent years has expanded to include subpopulations of patients with breast, pancreatic, and prostate cancers. Their potential to benefit patients with non-ovarian gynecologic cancers is being recognized. This review examines the underlying biological rationale for exploring PARPi in non-ovarian gynecologic cancers. We consider the clinical data and place this in the context of the current treatment landscape. We review the development of PARPi strategies for treating patients with endometrial, cervical, uterine leiomyosarcoma, and vulvar cancers. Furthermore, we discuss future directions and the importance of understanding HR deficiency in the context of each cancer type.

PARP inhibitors in non-ovarian gynecologic cancers Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the way ovarian cancer is treated, especially for patients whose tumors have specific genetic issues affecting their ability to repair DNA. Over time, PARPi are being used for certain groups of patients with breast, pancreatic, and prostate cancers. More recently, their potential to help people with other types of gynecologic cancers than ovarian have been studied. In this review, we explore the reasons behind looking into PARPi for these non-ovarian gynecologic cancers. We analyze the clinical data and compare it to the current treatment options available, focusing on endometrial, cervical, uterine leiomyosarcoma, and vulvar cancers. Additionally, we discuss about future directions and stress the importance of understanding the specific DNA repair context for each type of cancer. Especially, we discuss the tests that aims to define who may benefit from the drug, with focus on the homologous recombination deficiency.

Tumor-Infiltrating Lymphocytes in HER2-Low Breast Cancer.

INTRODUCTION: Tumor-infiltrating lymphocytes (TIL) is a predictive and prognostic biomarker for breast cancer (BC) HER2-positive and triple negative, but its presence in HER2-low tumors is unknown. We aimed to determine TIL levels in HER2-low tumors and its correlation with other clinicopathologic features. MATERIALS AND METHODS: We retrospectively analyzed all the pathology reports of breast surgeries of a tertiary hospital in Sao Paulo, Brazil, from January 2021 to March 2022. Inclusion criteria were stage I to III invasive BC, and exclusion criteria were nonmalignancies and neoadjuvant therapy. We assumed HER2 categories according to ASCO/CAP guidelines. TILs were defined as absent (0), low (1%-10%), intermediate (11%40%) and high (≥ 41%). Ki-67 levels were categorized as low (up to 19%) and high (≥ 20%). RESULTS: From 272 patients, 198 met the inclusion criteria. Histological grade 3 was found in 10, 19 and 47% of HER2-0, low, and positive tumors (P < .001). HER2-positive tumors had 82.6% of high Ki-67 levels, while HER2-negative and HER2-low showed 25.8% and 31.4% (P = .005). TILs in HER2-0, low, and positive tumors were, respectively, absent in 16.1%, 17.6%, and 8.7%; low in 70.2%, 52.9% and 34.8%; intermediate in 11.3%, 25.5% and 47.8%; and high in 2.4%, 3.9% and 8.7%. There was a statistically significant difference in TILs between HER2-negative versus HER2-positive groups (P < .001), but not between HER2-negative versus HER2-low, or HER2-low versus HER2-positive. CONCLUSION: TILs in HER2-low are marginally higher than HER2-negative, but significantly lower than HER2-positive levels. HER2-low tumors do not seem to significantly differ biologically from HER2-negative tumors.

Response to Pembrolizumab in Advanced Anal Squamous Cell Carcinoma With High TMB and PD-L1 and PD-L2 Amplification.

We report the case of a 44-year-old female with a prior diagnosis of Sjögren's syndrome who was treated for metastatic anal squamous cell carcinoma with second-line pembrolizumab and has achieved a sustained partial response after a follow-up of 13 months. Comprehensive genomic profiling was remarkable for PD-L1 and PD-L2 amplification and a high tumor mutational burden (19 mutations per megabase). To the best of our knowledge, we present the first report to correlate PD-L1 and PD-L2 amplification with good outcomes of immune checkpoint inhibition in metastatic anal squamous cell carcinoma.

Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity.

FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin-2-one derivatives, structurally similar to Sunitinib. Molegro Virtual Docker (MVD) software was utilized in docking analyses. The predicted model of the training group, considering nineteen amino acid residues, performed in Chemoface, achieved an R2 of 0.82, suggesting that the binding conformations of the ligands with FLT3 are reasonable, and the data can be used to predict the interaction energy of other FLT3 inhibitors with similar molecular patterns. The MolDock Score for energy for compound 1 showed more stable interaction energy (-233.25 kcal mol-1) than the other inhibitors studied, while Sunitinib presented as one of the least stable (-160.94 kcal mol-1). Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 can be highlighted as promising derivatives for synthesis and biological evaluation against FLT3. Furthermore, IAF79 can be considered to be a promising dual Aurora B/FLT3 inhibitor, and its molecular pattern can be exploited synthetically to search for new indolin-2-one derivatives that may become drugs used in the treatment of cancers, including AML.

Acute metabolic response to fasted and postprandial exercise.

The aim of this study was to analyze the acute metabolic response to exercise in fasting and postprandial. For this, ten individuals were submitted to an incremental treadmill test, with an initial speed of 5 and 1 km/h increments every minute, with no inclination, and a body composition assessment. After this 1st day, all volunteers were submitted to two experimental procedures (fasting and postprandial), with an aerobic exercise performed for 36 minutes at 65% of maximal oxygen consumption. At postprandial procedure, all subjects ingested a breakfast containing 59.3 g of carbohydrate (76.73%), 9.97 g of protein (12.90%), 8.01 g of lipids (10.37%), with a total energy intake of 349.17 kcal. An analysis of plasma concentration of triglycerides, lactate, and glucose was performed in two stages: before and after exercise. The Shapiro-Wilk test was used to verify the normality of the data. For analysis of glucose concentration, plasma lactate, and triglycerides, we used a repeated measures analysis of variance factorial 2×2, with Bonferroni multiple comparison test. The significance level of P<0.05 was adopted. The results indicated a maintenance level of glucose at fasting and a decrease in glucose concentration at postprandial exercise. Both conditions increase plasma lactate. Triglycerides also increased in the two experimental conditions; however, after exercise fasting, the increase was significantly higher than in the postprandial exercise. These data suggest that both exercises could increase plasma lactate and triglycerides. However, exercise performed in fasting condition decreases glucose concentration and increases triglycerides, even more than postprandial exercise.

Synthesis and biological evaluation of novel piperidine-benzodioxole derivatives designed as potential leishmanicidal drug candidates.

A novel series of ester and carbamate derivatives was synthesized and evaluated its activities against Leishmania amazonensis. All compounds exhibited weaker leishmanicidal activity than amphotericin B. However, results indicated that substituents on the aryl-acyl subunit are important for modulation of the leishmanicidal effect. The nitro derivative showed the highest activity of the series with an IC50 = 17.24 µM, and comparable potency to the 3,4-benzodioxole ester and n-hexyl carbamate derivatives. All compounds showed low toxicity against human cells. These results revealed interesting novel piperine-like molecular pattern for exploitation in search and development of effective and low toxic antileishmanial drug candidates.