Pretreatment with LCK inhibitors chemosensitizes cisplatin-resistant endometrioid ovarian tumors.

BACKGROUND: Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent. RESULTS: Kaplan-Meier (KM) plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p = 0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p = 0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed LCKi led to increased expression of phosphorylated H2A histone family X ([Formula: see text]-H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin led to significantly slowed tumor growth. CONCLUSIONS: We identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.

Fertility-Sparing Surgery for Early-Stage Cervical Cancer: A Systematic Review of the Literature.

OBJECTIVE: This systematic review aimed to evaluate oncologic and reproductive outcomes after fertility-sparing surgery (FSS) for early-stage cervical cancer (early CC). DATA SOURCES: Ovid MEDLINE, Ovid EMBASE, and Cochrane CENTRAL were searched from 1980 to the present using Medical Subject Headings terms; other controlled vocabulary terms; and keywords related to fertility, cervical cancer, and surgical techniques. METHODS OF STUDY SELECTION: A total of 2415 studies were screened, with 53 studies included. Studies reporting recurrences with a median follow-up of 12 months in early CC (International Federation of Gynecology and Obstetrics 2009 stages IA with lymphovascular space invasion, IB, or IIA) of traditional histologic type undergoing FSS were included. TABULATION, INTEGRATION, AND RESULTS: The studies were grouped by intervention, including vaginal radical trachelectomy (VRT), abdominal radical trachelectomy (ART), minimally invasive radical trachelectomy (MIS-RT), and conization or simple trachelectomy (ST), and studies involving neoadjuvant chemotherapy (NACT). Combined rates of recurrence (RR), cancer death (CDR), pregnancy (PR), and live birth (LBR) were calculated per procedure on the basis of all included studies that reported outcomes on that procedure. The results were as follows: VRT: RR 4%, CDR 1.7%, PR 49.4%, and LBR 65.0% ART: RR 3.9%, CDR 1.4%, PR 43.2%, and LBR 44.0% MIS-RT: RR 4.2%, CDR 0.7%, PR 36.2%, and LBR 57.1% Cone or ST: RR 4.2%, CDR 0.8%, PR 55.1%, and LBR 71.9% NACT: RR 7.5% and CDR 2.0% CONCLUSION: FSS of early CC with VRT, ART, or MIS-RT have comparable oncologic outcomes in carefully selected patients, with reproductive outcomes favoring VRT. Data on nonradical FSS with cone or ST are less robust but support similar oncologic outcomes to radical trachelectomy with fewer reproductive complications. NACT in this setting requires more investigation before routine implementation into practice.

Management of genitourinary syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy.

Genitourinary syndrome of menopause is a condition describing the hypoestrogenic effects on the female genitals and lower urinary tract leading to symptoms such as vaginal dryness, vulvar and vaginal burning, dyspareunia and dysuria. Genitourinary syndrome of menopause is experienced by over half of postmenopausal women, and is even more pervasive in women with cancer. Due to treatments such as surgery, chemotherapy, radiation, and hormonal therapy, women may experience early menopause resulting in earlier and more severe symptoms. Understanding the scope of this issue in female breast and gynecologic cancer survivors and identifying treatment options for this complex patient population are paramount. Tailored patient treatments include nonhormonal therapies (vaginal moisturizers, lubricants, pelvic floor physical therapy, dilator therapy, counseling), systemic and local hormonal therapies. Consensus recommendations by medical societies and associated evidence are reviewed, with emphasis on safety and efficacy of local vaginal hormonal therapies, and management variations noted depending on cancer type and characteristics. With knowledge and understanding of the unmet need associated with under-recognition and under-treatment of genitourinary syndrome of menopause, providers caring for women with cancer are in a position to improve the quality of life of their patients by providing safe and effective treatments.

Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer.

It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.