Purpose: Aberrant expression of different tight junction proteins, including the junctional adhesion molecule-A (JAM-A), has been frequently reported in association with tumor progression of several malignancies. To our knowledge, this is the first study examining the clinical significance of JAM-A gene expression in epithelial ovarian cancer. Methods: JAM-A expression levels in 44 epithelial ovarian cancer and 12 benign formalin-fixed paraffin-embedded samples were determined by reverse transcription quantitative polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic and prognostic potential of JAM-A. Associations between JAM-A expression and clinicopathological characteristics of epithelial ovarian cancer were analyzed using Fisher’s exact test. The Kaplan–Meier method and univariate Cox regression analysis were used for the survival analysis. P ⩽ 0.05 was considered statistically significant. Results: ROC curve analyses showed that JAM-A gene expression exhibits both diagnostic and prognostic performance in epithelial ovarian cancer (area under the curve (AUC) 0.640, 95% confidence interval (CI) 0.488, 0.792, sensitivity 43.18%, specificity 100% and AUC 0.621, 95% CI 0.427, 0.816, sensitivity 52.63%, specificity 85%, respectively). JAM-A expression was significantly associated with International Federation of Gynecologists and Obstetricians (FIGO) stage ( P =0.049) and the Kaplan–Meier method demonstrated that patients with high expression of JAM-A had significantly worse overall survival compared to patients with low JAM-A expression ( P =0.004). Moreover, univariate Cox regression analysis showed that FIGO stage, peritoneal metastasis, residual tumor and JAM-A expression were significantly associated with reduced overall survival in epithelial ovarian cancer. Conclusions: Our results indicate that high levels of JAM-A expression are associated with an advanced clinicopathological feature and may have diagnostic potential; also, it could be a predictor of poor overall survival in patients with epithelial ovarian cancer.
Background: Hormone receptor+/HER2- breast cancer is the most common subtype of breast cancer. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. ZN-c5 is a novel, orally bioavailable SERD with high potency and has demonstrated activity in estrogen-dependent tumor models. Methods: This Phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics and preliminary anti-tumor activity of ZN-c5 as monotherapy or in combination with palbociclib. In the Phase 1 portion evaluating ZN-c5 as monotherapy, participants were adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast, ER+/HER2- disease, and sensitive to endocrine therapy for metastatic disease (partial response [PR], complete response or stable disease [SD] lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment). ZN-c5 was administered orally and continuously in 28-day cycles until disease progression or unacceptable toxicity. Dose escalation cohorts of subjects were enrolled at several dose levels of ZN-c5, based on a modified 3+3 design. Enrollment in the Phase 1 ZN-c5 monotherapy dose escalation and expansion has been completed and results are presented. Phase 1 testing of ZN-c5 in combination with palbociclib and Phase 2 testing in monotherapy are ongoing and will be presented at a future meeting. Results: In Phase 1 monotherapy, a total of 56 female subjects were enrolled to receive ZN-c5 at dose levels of 50 mg once daily (QD, n=16), 75 mg QD (n=3), 100 mg QD (n=3), 75 mg twice daily (BID, n=6), 150 mg QD (n=15), 150 mg BID (n=3), or 300 mg QD (n=10). Median age was 58.5 years (range, 38 - 89) and ECOG performance status was 0 (55%) or 1 (45%). Subjects had a median of 2 prior therapies for advanced/metastatic disease (range, 0 - 9), with a median of 2 prior hormonal-based therapies (range, 0 - 6) and a median of 0 prior chemotherapies (range, 0 - 3). Twenty-six subjects (46%) received prior fulvestrant and 38 (68%) received a prior CDK4/6 inhibitor. Twenty subjects (38%) had a baseline ESR1 mutation. The cut-off date for this analysis was 11 May 2021. There was no increase in severity of treatment-emergent adverse events (TEAEs) with increase in dose level. No dose-limiting toxicities were reported. The most common TEAEs were nausea (30%), fatigue (25%), and arthralgia (20%). Grade 3 TEAEs reported in > 1 subject were gamma-glutamyltransferase (GGT) increased and hyponatremia (2 subjects each); no Grade 4 TEAEs were reported. Among treatment-related events, the most common were hot flushes and nausea (14% each); the only Grade 3 events were GGT increased and hypersensitivity in 1 subject each. ZN-c5 was rapidly absorbed, with a median Tmax of 2 to 4 hours. AUC and Cmax on Days 1 and 15 were less than dose proportional. No ZN-c5 accumulation after 15 days of dosing was observed. Confirmed PRs have been observed in 2 subjects (at 150 and 300 mg QD, respectively), and 14/45 (31%) evaluable subjects have experienced clinical benefit (PR or SD ≥ 24 weeks). Five of the 14 subjects with long SD received prior fulvestrant. Median progression-free survival (PFS) was 3.8 months (95% CI: 3.2, 5.3). Conclusions: In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib. Citation Format: Kevin Kalinksy, Vandana Abramson, Pavani Chalasani, Hannah M. Linden, Jasmina Alidzanovic, Rachel M. Layman, Živko Vranješ, Julie R. Nangia, Katherine D. Crew, Zoran Andric, Marijana Milovic-Kovacevic, Jasna Trifunovic, Jose Suarez, Matt Suster, Mieke Ptaszynski, Joanne Mortimer. ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-02.
Background Therapeutic options for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (mBC) are developing rapidly. This study aimed to determine the differences in the survival outcomes of patients with HER2-positive mBC in relation to access to anti-HER therapy at 3 oncology centers in upper-middle-income countries (UMICs) and 1 oncology center in a high-income country (HIC). Material/Methods We retrospectively identified 42 patients from Croatia (HIC), 71 patients from Serbia (UMIC), and 57 from Bosnia and Herzegovina (UMIC) diagnosed with HER2-positive mBC who were treated between January 2015 and December 2020. The pathohistological features of the tumors were obtained from the pathological findings, which were made according to standard procedures for each center. Patients were treated depending on the availability of therapy, which differed for centers in different countries. We evaluated disease-free survival, progression-free survival, and overall survival (OS) based on the availability of first- and second-line anti-HER2 therapy in UMICs vs HIC. Results OS in first-line therapy was better in patients treated with dual HER2 blockade than in patients treated without dual HER2 blockade, P <0.001. OS in second-line therapy was significantly better in patients treated with trastuzumab emtansine than in patients treated with other reported regimens, P =0.004. Conclusions Results of our study showed superior survival among patients who were treated with dual first-line HER2 therapy as well as second-line trastuzumab emtansine therapy than in those patients in other centers where these drugs were not available. Raising awareness about this could help improve the situation.
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