Novel Molecular Targets in Endometrial Cancer: Mechanisms and Perspectives for Therapy.

Endometrial cancer (EC) has a high epidemiological impact with incidence and mortality rising worldwide. In recent years, the integration of the pathologic and molecular classification has provided relevant information to understand the heterogeneity in the biology of EC, which led to the evolution in the management of patients. Currently, therapeutic breakthroughs have been made in advanced EC to improve oncologic outcomes, with efforts to include patient reported outcomes. Precision and personalized medicine are under way in EC exploring different combination approaches to target cross-talk pathways, cancer cell microenvironment, and metabolic vulnerabilities and improve drug delivery. Yet, collaborative efforts are needed to face the challenges in practice by refining patient selection, ideal biomarker identification, and de-escalation of therapies according to emerging molecular and genomic features of EC.

Mirtazapine as Appetite Stimulant in Patients With Non-Small Cell Lung Cancer and Anorexia: A Randomized Clinical Trial.

Importance: Currently there is no standard therapy to improve cancer-related anorexia, hampering survival. Mirtazapine has been suggested as a feasible option in this context. Objectives: To assess the effect of mirtazapine on appetite and energy consumption in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This randomized, double-blind, placebo-controlled clinical trial including adults was performed in a tertiary cancer care center from August 2018 to May 2022 with a follow-up of 8 weeks. Overall, 134 patients were screened; 114 were assessed for eligibility and 28 were excluded. Interventions: Patients were randomized in a 1:1 ratio to receive mirtazapine, 15 mg, or placebo for 2 weeks followed by a dose escalation to 30 mg until week 8 or placebo. Both groups received nutritional assessment and dietary advice. Main outcomes and measures: Appetite was assessed by the Anorexia Cachexia Scale and energy intake. Dietary parameters were evaluated at baseline, 4 weeks, and 8 weeks, with a 24-hour dietary recall, and energy quantification based on the Mexican system of nutritional equivalents. Results: A total of 86 patients met the inclusion criteria and were randomized to the placebo (n = 43) or the mirtazapine group (n = 43). The mean (SD) age was 63.5 (11.2) years, 41 were women (57.7%) and had adenocarcinoma, Eastern Cooperative Oncology Group performance status scale score of 1, stage IV NSCLC, and were receiving first-line treatment. Baseline characteristics were similar between groups. There was no difference in appetite scores in patients who received mirtazapine or placebo after 4 and 8 weeks. After 4 weeks, mirtazapine significantly increased energy intake (379.3 kcal; 95% CI, 1382.6-576.1; P < .001) including proteins (22.5 g; 95% CI, 11.5-33.4; P = .001), carbohydrates (43.4 g; 95% CI, 13.1-73.8; P = .006), and fats (13.2 g; 95% CI, 6.0-20.4; P = .006). Fats intake was significantly higher in patients in the mirtazapine group (14.5 g vs 0.7 g; P = .02) after 8 weeks. The mirtazapine group significantly decreased the proportion of patients with sarcopenia (82.8% vs 57.1%, P = .03) at 8 weeks. Patients on mirtazapine tolerated the treatment well, but reported a higher perception of nightmares at 2 weeks based on a 10 cm VAS score (0 [25th-75th percentile, 0-1] vs 0 [25th-75th percentile, 0-0] in the control group; P = .009) but this finding was nonsignificant after 4 and 8 weeks. Conclusion and Relevance: In this randomized clinical trial of patients with advanced NSCLC, there was no difference in appetite scores in all patients who received mirtazapine or placebo, but the mirtazapine group had a significant increase in energy intake through the 4- and 8-week follow-up, mainly in fat intake, which is a better and crucial source of energy. The addition of mirtazapine in the treatment of patients with advanced NSCLC and anorexia may help these patients achieve their energy requirements and improve health-related quality of life, specifically emotional and cognitive functioning. Trial Registration: ClinicalTrials.gov Identifier: NCT04748523.

Methodical Manipulation of the TME in Ovarian Cancer.

The complex interplay between ovarian cancer cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in ovarian cancer. See related article by Tavira et al., p. 176.

Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma.

The identification of Epidermal Growth Factor Receptor (EGFR) mutations in lung adenocarcinoma has facilitated the development of personalized medicine based on oncogenic drivers. EGFR-Tyrosine Kinase Inhibitors (TKIs) are part of the targeted therapy; they impede the phosphorylation of the intracellular tyrosine kinase component of EGFR and consequently block signal transduction pathways. These drugs inhibit the proliferation and survival of tumor cells, leading to long-term progression-free survival and overall survival. Diarrhea is one of the most frequent adverse events associated with EGFR-TKIs, affecting at least 18% of patients and reaching up to 95% in some cases. Diarrhea should be managed carefully given its association with important complications, treatment interruptions, and dose reductions. Moreover, nutritional status and quality of life (QoL) can deteriorate due to severe diarrhea. Changes in diet, such as increment of fiber, supplementation with glutamine, and use of probiotics, may contribute to a decrease in the incidence of diarrhea. Improving the control of diarrhea can provide a significant benefit to the QoL of patients.

Case report: Osimertinib administration during pregnancy in a woman with advanced EGFR-mutant non-small cell lung cancer.

Lung cancer (LC) is one of the most common causes of death worldwide. The identification of oncogene-addicted driving mutations suitable for targeted therapy has improved clinical outcomes in advanced diseases. Clinical trials, on the other hand, rarely involve vulnerable groups such as pregnant women. We report a 37-year-old woman with advanced non-small cell lung cancer (NSCLC) harboring an exon 19 deletion of EGFR treated with afatinib. After the initial treatment, the patient achieved a complete response and had an unplanned pregnancy. Targeted therapy was withheld during the first trimester and resumed with osimertinib in the second trimester in which the patient developed oligohydramnios and intrauterine growth restriction (IUGR) of the baby. Osimertinib was delayed at two different times during the third trimester with complete resolution of the oligohydramnios. The baby was born at 37.3 weeks of gestation (WOG) with no signs of congenital disorders. After delivery, the mother restarted osimertinib and maintained a complete response. This case suggests that osimertinib could be an acceptable option for tumor control during pregnancy in EGFR-mutant NSCLC. This information do not replace current recommendations for avoiding pregnancy and promoting contraceptive usage in patients receiving any cancer therapy.

Overcoming PARP inhibitor resistance in ovarian cancer.

Ovarian cancer (OC) is one of the most lethal tumors in women, mostly diagnosed at advanced stages. Standard of care is based on surgery and platinum-based chemotherapy which provides high rates of response, although most patients will relapse. Poly(ADP-ribose) polymerase inhibitors (PARPi) have recently been incorporated in the treatment strategy for high-grade OC, particularly for those with defects in DNA repair pathways (homologous repair deficiency (HRd)). However, some tumor cells may not respond and some others will develop mechanisms of resistance to adapt. The most known mechanism of PARPi resistance is the reversion of HRd to homologous repair proficiency driven by epigenetic and genetic changes. Ongoing research is exploring different agents that are trying to re-sensitize tumor cells,overcome or bypass resistance to PARPi. Current investigations are focused on agents that target replication stress and DNA repair pathways, improve drug delivery, and target other cross-talk pathways. A crucial challenge in practice will be to identify and select patients for the appropriate therapy or combination strategies. However, efforts are needed to decrease overlapping toxicity and define the correct schedule timing of dosing to maximize the therapeutic index.

Modifying factors of PD-L1 expression on tumor cells in advanced non-small-cell lung cancer.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression predicts immunotherapy utility in nononcogenic addictive lung adenocarcinoma (ADC). However, its reproducibility and reliability may be compromised outside clinical trials. This study aimed to evaluate factors associated with PD-L1 expression in lung ADC. METHODS: This observational study assessed 547 tumor samples with advanced lung ADC from January 2016 to December 2020 in a single cancer institution. Tumor samples were stained by at least one approved PD-L1 clone, SP263 (Ventana) or 22C3 (Dako), and stratified in tumor proportion score (TPS) <1%, 1-49%, or ≥50%. RESULTS: Of all the tumor samples, positive PD-L1 staining was higher in poorly differentiated tumors (67.3% vs. 32.7%, p < 0.001). Analytical factors associated with a PD-L1 high expression (TPS ≥ 50%) were the SP263 clone (19.6% vs. 8.2%, p < 0.001), time of archival tumor tissue <12 months (15.3% vs. 3.8%, p = 0.024), whenever the analysis was performed in the most recent years (2019-2020) (19.0% vs. 8.3%, p < 0.001), and whenever the analysis was performed by pathologists in the academic setting (Instituto Nacional de Cancerologia, INCan) (19.9% vs. 11.9%, p = 0.001). In the molecular analysis, EGFR wild-type tumors had an increased proportion of PD-L1 positive and PD-L1 high cases (60.2% vs. 47.9%, p = 0.006 and 17.4% vs.8.5%, p = 0.004). A moderate correlation (r = 0.69) in the PD-L1 TPS% was observed between the two different settings (INCan vs. external laboratories). CONCLUSION: Clinicopathological factors were associated with an increased PD-L1 positivity rate. These differences were significant in the PD-L1 high group and associated with the academic setting, the SPS263 clone, time of archival tumor tissue <12 months, and a more recent period in the PD-L1 analysis.

Durvalumab After Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer: Inferior Outcomes and Lack of Health Equity in Hispanic Patients Treated With PACIFIC Protocol (LA1-CLICaP).

Objectives: To compare the rate disparity between outcomes (overall survival (OS), progression-free survival (PFS), and safety) of concurrent chemoradiation (cCRT) followed by durvalumab in two patient cohorts with locally advanced (LA) stage III non-small cell lung cancer (NSCLC), one non-Hispanic White (NHW), and the other Latin-American. Methods: A multicenter retrospective study was performed, including 80 Hispanic and 45 NHW LA stage III NSCLC patients treated with cCRT followed by durvalumab. Both cohorts were analyzed in terms of main outcomes (OS, PFS, and safety) and compared between them and with the PACIFIC trial population outcomes. The efficacy-effectiveness gap was assessed using an efficacy-effectiveness (EE) factor that was calculated by dividing each cohort median overall survival by the corresponding reference OS from the PACIFIC trial. In both cohorts, results of PD-L1 testing were recorded, and the main outcomes were compared according to PD-1 expression levels (≥50%, 1-49%, and <1%). Results: For the entire population (N=125), the overall response rate (ORR) was 57.6% (N=72), and 18.4% (N=25) achieved stable disease. OS was 26.3 months (95%CI 23.9-28.6), and PFS was 20.5 months (95%CI 18.0-23.0). PFS assessed by ethnicity showed a median for the Hispanic population of 19.4 months (95%CI 16.4-22.5) and 21.2 months (95%CI 17.2-23.3; p=0.76) for the NHW group. OS by race showed a significant difference in favor of the NHW group, with a median OS of 27.7 months (95%CI 24.6-30.9) vs. 20.0 months (95%CI 16.4-23.5) for Hispanics. (P=0.032). Unadjusted 12-month and 24-month OS was 86.6% (95%CI 79.9-88.0) and 46.6% (95%CI 40.2-48.3) for NHW compared to 82.5% (95%CI 77.1-84.2) and 17.5% (95%CI 15.6-24.5) in Hispanics. NHW had an EE factor of 0.78 and Hispanics had 0.58, showing a reduction in survival versus NHW and PACIFIC of 20% and 42%, respectively. HR for the OS among NHWs and Hispanics was 1.53 (95%CI 1.12-1.71; P=0.052) and 2.31 (95%CI 1.76-2.49; P=0.004). Fifty-six patients (44.8%) had some degree of pneumonitis due to cCRT plus durvalumab. There was no difference in the proportion of pneumonitis according to race (P=0.95), and the severity of pneumonitis was not significantly different between Hispanics and NHWs (P=0.41). Conclusions: Among patients with LA stage III NSCLC, NHW had better survival outcomes when compared to Hispanics, with an OS that seems to favor the NHW population and with an EE factor that shows a shorter survival in Hispanics compared with NHW and with the PACIFIC trial group.

Prevalence and Molecular Profile of Breast Carcinoma Using Immunohistochemistry Markers in Mexican Women.

BACKGROUND: In Mexico, breast cancer is the leading cause of death by malignant tumors in women aged 20 and older. The World Health Organization estimates that 69% of deaths caused by breast cancer occur in developing countries. Little is known about the prevalence of breast carcinoma in Mexico and its molecular subclassification. METHODS: This retrospective cross-sectional study included patients who underwent a mastectomy (single, radical or lumpectomy) or a breast tumor biopsy (core-needle or excisional) from January 2002 to December 2018. The primary purpose of the study was to determine the prevalence and molecular profile of breast in comprehensive cancer center in Mexico and compare our results with those published in the US. This study was approved by our scientific and bioethical committee. RESULTS: The final analysis included 379 patients. The youngest patient was 23 years old and the oldest patient was 89; the mean age at diagnosis was 54.63 years. Patients of 40 years old or younger accounted for 48 of the cases (12.66%) and those older than 40 accounted for 331 of the cases (87.33%). The molecular subclassification showed luminal A subtype in 139 cases (36.67%), luminal B subtype in 143 cases (37.73%), human epidermal growth factor receptor 2-positive carcinomas in 32 cases (8.44%) and triple-negative carcinomas in 65 cases (17.15%). Diabetes mellitus was present in 43 patients (11.34%), hypertension in 78 patients (20.58%), obesity in 82 patients (21.63%) and 66 patients reported being treated with exogenous hormone therapy (17.41%). CONCLUSIONS: Breast carcinoma occurs at an earlier age in Mexican women compared to women in the US. Hormone-positive tumors were found to be more prevalent in older patients, while high-grade tumors were more frequently identified in younger patients.

Breast Metastasis of Gastric Signet Ring Cell Carcinoma: A Case Report and Literature Review.

Breast metastasis from gastric signet ring cell carcinoma is extremely rare in clinical practice. The estimated incidence is 0.5-1.3%. There are few cases reported in the literature (approx. less than 60) of breast metastasis from gastric signet ring cell carcinoma, and due to the rare association between gastric cancer and its extension to the breast, it is difficult to establish the diagnosis. Clinical history, histological findings, and immunohistochemical markers are helpful in distinguishing primary breast cancer from breast metastasis of gastric cancer. The treatment for breast metastasis from gastric carcinoma remains controversial. The prognosis of breast metastasis from gastric carcinoma is generally poor. We report a case of breast metastasis of gastric signet ring cell carcinoma in a 38-year-old woman. She started chemotherapy with ramucirumab, paclitaxel, and irinotecan. Three months later, a combined 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography showed a complete response. This is the first reported case of breast metastasis from gastric signet ring cell carcinoma with a complete response.

Myoepithelial Carcinoma Arising in a Plasmacytoid Myoepithelioma of the Parotid Gland Synchronized with Melanoma: A Case Report and Review of the Literature.

Myoepithelial carcinoma, also known as malignant myoepithelioma, is considered an extremely rare (0.45-1%) malignant salivary gland neoplasm. Approximately 100 cases have been reported in the English-language literature on myoepithelial carcinoma. The majority of the myoepitheliomas described in the literature have been benign, and the malignant counterpart is considered rare (<1%). Such a tumor may appear de novo or rarely develop from a preexisting pleomorphic adenoma (<20%), and in exceedingly rare cases (<0.5%), it has arisen from a benign myoepithelioma (i.e., plasmacytoid myoepithelioma). To our knowledge, no case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma has been reported to date. The treatment of myoepithelial carcinoma has been mainly surgical, including wide excision with free margins, with or without nodal dissection. The roles of chemotherapy and radiotherapy have not yet been established. We report a case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma in a 40-year-old woman. In our case, a complete response was achieved with surgery followed by adjuvant chemotherapy based on carboplatin and paclitaxel concurrent with radiotherapy.

Neuroendocrine Tumor of the Common Bile Duct: Case Report.

Carcinoma of the extrahepatic biliary tract accounts for <2% of all cancers. Neuroendocrine tumor of the extrahepatic bile duct is very rare, and there are <200 cases reported since 1959. The preoperative diagnosis is infrequent (5.12%). The definite diagnosis relies on postoperative pathology which utilized immunohistochemistry study on many biomarkers to diagnose the histological subtypes of neuroendocrine neoplasms, such as chromogranin A, synaptophysin, and neuron-specific enolase. When the primary tumor has no metastases, radical removal of the lesion appears as curative treatment. The treatment of the carcinoid syndrome or other functioning syndrome is the first priority. We report a case of a 12-year-old Mexican woman with neuroendocrine tumor of the extrahepatic bile duct (common bile duct neuroendocrine tumor) seen in our hospital. Resection of the common bile duct, cholecystectomy, end to side Roux-en-y hepaticojejunostomy, and portal lymphadenectomy was performed. A review of the pertinent literature was performed. Given the rarity of the disease, treatment principles are based mainly on retrospective series and case reports. We present the eighth case in adolescence in the literature.

Acute Cardiac Tamponade Secondary to Cardiac Vascular-Type Pleomorphic Leiomyosarcoma: Case Report.

Soft tissue sarcomas represent <1% of all neoplasms. Leiomyosarcomas comprise only 5-7% of cases, and only 2% of these are vascular. Vascular leiomyosarcomas are extremely rare and represent only 0.001% of all neoplasms, the venous type being up to 5 times more frequent. Arterial leiomyosarcomas most frequently affect the great vessels, being fatal in most cases. In the reported cases of arterial leiomyosarcomas, the most frequently affected site is the pulmonary artery. We present the clinical case of 2 patients (a 42-year-old woman and a 36-year-old man) with a diagnosis of arterial pleomorphic leiomyosarcoma that conditioned cardiac tamponade as the initial manifestation. As it is an exceptionally rare neoplasm and with few cases reported in the literature, it is important to identify and describe this pathology which, due to the impossibility of offering surgical treatment, represents a therapeutic challenge.