Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor.

PURPOSE: Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS: In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS: Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION: In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

Serum Levels of Hcy, sST2 and CA-125 in CHF Patients and Their Correlation with Cardiac Function Classification.

BACKGROUND: The relationships between serum levels of homocysteine (Hcy), soluble stromelysin 2 (sST2), and tumor-associated cancer antigen 125 (CA-125) and heart failure requires further investigation. The aim of the present study was to evaluate the levels of Hcy, sST2 and CA-125 in patients with congestive heart failure and to correlate these with cardiac function, thereby providing a reference for the clinical diagnosis and treatment of heart failure. METHODS: Seventy patients with chronic heart failure (CHF) diagnosed between August 2020 and July 2022 were classified into heart failure groups II (n = 25), III (n = 23) and IV (n = 22). Seventy individuals with normal physical examination results were selected as the healthy group. Serum Hcy, sST2 and CA-125 levels for all participants were evaluated and correlated with each other and with cardiac function classification. The diagnostic value of individual Hcy, sST2, CA-125 levels for CHF was evaluated, as well as a combination of these factors. RESULTS: Hcy, sST2, and CA-125 levels were lower in the healthy group than in the heart failure group. Moreover, a progressive increase in Hcy, sST2, and CA-125 levels were observed in heart failure groups II, III, and IV. Individual Hcy, sST2 and CA-125 levels, as well as a combination of these factors, were significantly correlated with cardiac function classification (p < 0.05). Hcy, sST2 and CA-125 levels each showed diagnostic value for CHF, with the three combined having the best diagnostic value. CONCLUSIONS: Abnormally high levels of Hcy, sST2 and CA-125 occur in CHF patients and are positively correlated with cardiac function classification. Individual levels of these factors, and particularly a combination of the three, show good sensitivity and specificity for CHF diagnosis that could be widely used in clinical practice.

MUC16 promotes triple-negative breast cancer lung metastasis by modulating RNA-binding protein ELAVL1/HUR.

BACKGROUND: Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. METHODS: The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. RESULTS: MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. CONCLUSIONS: Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

Development of Triple-Negative Breast Cancer-Targeted Liposomes with MUC16 Binding Peptide Ligand in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is a highly malignant tumor that does not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). As molecular approaches to these targets have limited clinical utility in TNBC, novel strategies for the treatment of TNBC are urgently needed. MUC16 (Mucin-16) is a glycoprotein involved in cell proliferation and apoptosis and is overexpressed in breast cancer. To develop a clinically available strategy for TNBC treatment, we synthesized a MUC16 targeted peptide (EVQ)-grafted lipid derivative, EVQ-(SG)5-lipid, and prepared EVQ-(SG)5/PEGylated liposomes of 100 nm by size and a slightly negative ζ-potential value. Thus, we aimed at investigating the association between EVQ-(SG)5/PEGylated and TNBC cell lines by interacting with MUC16 using an in vitro model. In addition, we aimed at exploring the intracellular distribution and cellular uptake pathway of EVQ-(SG)5/PEGylated liposomes as novel drug delivery carriers for TNBC.

Ovarian cancer: the duplicity of CA125 measurement.

Since it was first described in 1981, CA125 has held an important role in monitoring patients with ovarian cancer. CA125 is elevated in 80% of patients with epithelial ovarian cancer at initial diagnosis and correlates well with response to therapy. CA125 monitoring is used for the follow up of patients with epithelial ovarian cancer, and elevations in CA125 measurements often antedate any signs, symptoms or radiographic evidence of disease by several months. Unfortunately, data favoring early therapeutic intervention for recurrent ovarian cancer is lacking, especially in patients with isolated CA125 elevations. In asymptomatic patients, elevations in CA125 have been associated with considerable anxiety and deterioration in quality of life without any significant gains in survival. Patients with ovarian cancer should, therefore, be counseled regarding the advantages and shortcomings of intensive CA125 testing. While some patients may benefit from early detection of recurrent disease and be candidates for secondary cytoreductive surgery, others may choose to delay therapy until they develop symptoms of disease recurrence. The results of a clinical trial suggest that withholding treatment in the event of isolated rising CA125 levels will not negatively impact these patients overall survival, highlighting the need for improved salvage therapies for recurrent ovarian cancer.

On a new strategy of preventive oncology.

The etiology of cancer is much wider than separately taken causal agent and rests against the most complicated interrelation and mutuality of many external and internal influences. Our researches with use of fluorescing antibodies to AFP, CEA and Ca-19-9 have shown that they are intensively besieged on a surface of cultivated malignant cells. It is the basic mechanism of tolerance and immunological escape, which is similar to pregnancy when "the maximal immunological most favored status" to developing fetus (semiallogenic transplant) is provided. The earliest revealing of first cancer cells, before steady community of cells and tumor angiogenesis were formed, has particular importance in the fight against cancer. The necessity of the specific completion of the weakened antineoplastic resistibility of people from high oncological risk groups is substantiated. The activity in this direction brought forth the design of embryonic anti-tumor modulator (EATM). EATM is composed of a wide pool of fetal proteins and proteoglycans isolated exceptionally from normal embryonic substances.

Antitumor activity of specific immunotherapy with mucin containing CA 125 antigen in mice with CaO 1 ovarian carcinoma.

Experiments in CBA mice with transplanted CaO 1 ovarian carcinoma possessing common antigenic determinants with human ovarian carcinoma showed that specific immunotherapy with mucin containing CA 125 antigen inhibited tumor growth by 60% and prolonged animal lifespan by 40-60% in comparison with the control. The correlation coefficient between the tumor size and antibody titer after injection of mucin was -0.4 for IgM and -0.6 for IgG. Titration of IgG may be used for monitoring of the efficiency of specific immunotherapy.

Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125--results in immune and clinical responses in breast cancer patients.

In breast cancer there is often overexpression of the breast cancer antigen CA15-3, the carcinoembryonic antigen (CEA) and the ovarian cancer antigen CA125, which makes them potential target antigens for immunotherapy. In this study, we used a multi-antigen vaccine, which included the following antigens: autologous breast cancer cells (AUTOC), allogeneic breast cancer MCF-7 cells (ALLOC), and the tumor associated antigens CA15-3, CEA and CA125, plus low doses of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin 2 (IL-2). Forty-two breast cancer patients received weekly subcutaneous vaccination at the 1st, 2nd, 3rd, 7th, 11th and 15th weeks. Their lymphocyte proliferative responses to AUTOC, ALLOC, CA15-3, CEA and CA125 were tested in lymphocyte blastogenesis assays (LBA) before and after vaccination. The disease stage and serum CA15-3, CEA and CA125 concentrations were also determined pre- and post-vaccination. We found that the vaccine was safe, and the only major side effects were swelling at the site of injection, muscle pain, and weakness or fatigue. The vaccine induced a significant increase in post-vaccination lymphocyte proliferative responses to AUTOC, CA15-3, CEA and CA125 but not ALLOC, compared to pre-vaccination (p < 0.05, p < 0.01, p < 0.05, p < 0.01 and p > 0.05, respectively, a paired t Test). Computed tomography (CT), ultrasound or bone scan showed evidence of disease improvement in 2 (12%) patients after vaccination. Hepatic metastases were reduced in size and number and some actually disappeared one patient. Metastatic disease in the L5 vertebra and the skull decreased in size and some osteolytic sites completely healed in a second patient. In addition, 7 patients (44%) had stable disease and 7 patients (44%) had disease progression. We did not find vaccination significantly reduced serum tumor markers CA15-3, CEA and CA125 of these breast cancer patients. These results suggest that the vaccine mixture of autologous and allogeneic breast cancer cells and tumor associated antigens plus GM-CSF and IL-2 can be administered safely to breast cancer patients and there is evidence for improved immunity and clinical efficacy.

How to overcome the disturbing effects of human anti-mouse antibodies (HAMA) on in vitro assays.

The development of human anti-mouse antibodies (HAMA) is a common immune response in patients with ovarian carcinoma after repeated injections of murine anti-CA 125 monoclonal antibodies for immunoscintigraphy. As a tumor marker with significant diagnostic value CA 125 is routinely measured in the follow-up of tumor patients by immunoradiometric assays (IRMA) based on murine anti-CA 125 monoclonal antibodies. HAMA may cause false-positive findings in a CA 125-IRMA. In this report our group demonstrates a simple way of eliminating HAMA by protein A/G affinity chromatography allowing the reliable detection of the tumor marker CA 125 in the serum of patients with ovarian carcinoma.