Janine M. Lombard

Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy

BACKGROUND Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).

Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice

During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice.

Supportive care of women with breast cancer: key concerns and practical solutions.

Patients diagnosed with breast cancer may have supportive care needs for many years after diagnosis. High quality multidisciplinary care can help address these needs and reduce the physical and psychological effects of breast cancer and its treatment. Ovarian suppression and extended endocrine therapy benefits are associated with vasomotor, musculoskeletal, sexual and bone density‐related side effects. Aromatase inhibitor musculoskeletal syndrome is a common reason for treatment discontinuation. Treatment strategies include education, exercise, simple analgesia and a change to tamoxifen or another aromatase inhibitor. Chemotherapy‐induced alopecia may be a constant reminder of breast cancer to the patient, family, friends, acquaintances and even strangers. Alopecia can be prevented in some patients using scalp‐cooling technology applied at the time of chemotherapy infusion. The adverse impact of breast cancer diagnosis and treatment on sexual wellbeing is under‐reported. Identification of physical and psychological impacts is needed for implementation of treatment strategies. Fear of cancer recurrence reduces quality of life and increases distress, with subsequent impact on role functioning. Identification and multidisciplinary management are key, with referral to psychosocial services recommended where indicated. The benefits of exercise include reduced fatigue, better mental health and reduced musculoskeletal symptoms, and may also include reduced incidence of breast cancer recurrence. Identification and management of unmet supportive care needs are key aspects of breast cancer care, to maximise quality of life and minimise breast cancer recurrence.

Ovarian hormones through Wnt signalling regulate the growth of human and mouse ovarian cancer initiating lesions

Ovarian cancer (OC) is the most deadly gynaecological disease largely because the majority of patients are asymptomatic and diagnosed at later stages when cancer has spread to other vital organs. Therefore, the initial stages of this disease are poorly characterised. Women with BRCA1/2 mutations have a genetic predisposition for developing OC, but not all of these women develop the disease. Epidemiological findings show that lifestyle factors such as contraceptive use and pregnancy, a progesterone dominant state, decrease the risk of getting OC. How ovarian hormones modify the risk of OC is currently unclear. Our study identifies activated Wnt signalling to be a marker for precursor lesions of OC and successfully develops a mouse model that mimics the earliest events in pathogenesis of OC by constitutively activating βcatenin. Using this model and human OC cells, we show that oestrogen promotes and progesterone suppresses the growth of OC cells.

Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.

Changes in medical oncology admissions for the management of breast cancer complications: An Australian institution's experience

Aims:  There is a scarcity of data regarding medical hospitalizations for breast cancer. The aim was to determine whether the burden of inpatient care for breast cancer was declining.

Early detection of treatment induced cardiac toxicity – can we do better?

As the treatment of many malignancies has improved over the last few decades, more than 60% of patients with a new cancer diagnosis will live at least 5 years. The early detection and possible prevention of treatment (chemotherapy or targeted therapy)-related toxicity to avoid shortand long-term side effects has thus become increasingly relevant to many patients and their treating physicians. Cardiac toxicity can be caused by a number of chemotherapy drugs or targeted therapies. In early breast cancer anthracyclines remain one of the most important drugs in terms of this side effect. Although there has been a shift towards non-anthracycline containing regimens for early breast cancer, they still remain the backbone of most regimens used in intermediate to high risk disease. A number of other agents are also of importance in terms of cardiac risk including trastuzumab, lapatinib and new antibody-drug conjugates such as TDM-1. The mechanisms by which these agents cause cardiac toxicity are still not well defined. The terms “Type I” and “Type II” have been used in chemotherapy-related cardiac dysfunction. Type I, associated with the anthracyclines, results in variable myocyte destruction and clinical heart failure. Type II can be associated with a loss of contractility (potentially temporary) that is less likely to be associated with myocyte death or clinical heart failure and is more likely to be reversible. This appears to fit the pattern observed with trastuzumab. Treatment-related cardiac toxicity is usually monitored via serial assessment of left ventricular ejection fraction either by echocardiography or radionuclide ventriculography. These modalities however detect abnormalities once there has already been myocardial damage. Markers that predict for myocardial damage allowing earlier cessation of the toxic agent and easy and reliable monitoring of progress are desirable. A number of candidate biomarkers have been studied including troponin I and T, creatinine kinase MB isoform and N-terminal pro-B type natriuretic peptide (NT-proBNP). Cardiac troponin I (cTnI) and T (cTnT) are regulatory proteins that control the calcium-mediated interaction of actin and myosin. Cardiac injury causes disruption to the cardiac myocyte membrane integrity leading to their presence in the extracellular space. cTnI is cardiospecific as opposed to cTnT which can be found in skeletal muscle. The isomers of creatinine kinase reside in the cytosol and facilitate the transport of high-energy phosphates into and out of mitochondria. Most circulating CK-MB originates from cardiac myocytes. Cardiac troponin assays have largely superseded CK-MB, where available, in the diagnosis of acute myocardial damage/ infarction. Brain natriuretic peptide (BNP) was first identified as a natriuretic hormone released from the ventricles in response to high ventricular filling pressures. NT-proBNP is the biologically inert product formed from the prohormone proBNP. The plasma concentrations of NT-proBNP are increased in patients with asymptomatic and symptomatic left ventricular dysfunction. Population studies have shown its utility in predicating cardiovascular events. In the current issue Kittiwarawut et al investigated the utility of these proposed biomarkers in predicting for treatment related cardiac toxicity by prospectively studying 52 chemotherapy-naive patients without an underlying cardiac history undergoing treatment with doxorubicin and cyclophosphamide for early breast cancer. Their results showed a statistically significant increase in the level of serum NT-proBNP when measured prior to the second cycle of chemotherapy in the 11 patients who later developed grade I or II cardiac toxicity as measured by the National Cancer Institute common toxicity criteria version 2.0. This increase was not significantly sustained at the completion of treatment (12 weeks). Other recent papers in this area have provided conflicting results. NT-proBNP was found to be significantly elevated 24 hours following trastuzumab infusion, whereas Troponin I was not, in a small study of women already receiving trastuzumab. The study was not designed to assess if elevated biomarkers predicted for cardiac toxicity. In contrast a small study of women diagnosed with breast cancer that received anthracyclines and trastuzumab had their biomarkers assessed at 0, 3 and bs_bs_banner

Adipose-Derived VEGF–mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer. Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.

Nucleotide excision repair protein ERCC1 and tumour-infiltrating lymphocytes are potential biomarkers of neoadjuvant platinum resistance in high grade serous ovarian cancer

OBJECTIVE ERCC1 is a nucleotide excision repair protein that may have a role in drug resistance in high grade serous ovarian cancer (HGSOC). We hypothesized that ERCC1 expression and tumour infiltrating lymphocytes (TILS) are induced by chemotherapy in HGSOC, which may be prognostically useful. METHODS 115 HGSOC patients were used for this study. 92 (80%) of the tissue analysed had not been exposed to platinum chemotherapy. The remaining 20% (n = 23) of cases received combination or monotherapy with carboplatin before tissue was collected. Immunohistochemistry was used to score for ERCC1 expression and morphology to score for TILs. Correlation analysis of all clinical parameters, TILs and ERCC1 and Kaplan-Meier survival analysis was performed using the ERCC1 and TILs scoring parameters (0, 1, 2 or 3). RESULTS ERCC1 expression was 2-fold higher in the neoadjuvant chemotherapy group compared to the primary cytoreductive surgery group (p < 0.0001). The mean overall survival for the neoadjuvant group with high ERCC1 was 141.6 ± 20.2 months which was significantly longer than absent ERCC1 survival of 61 + 22.6 months (p = 0.028). ERCC1 score strongly correlated with TILs score across the whole cohort (0.349, p = 1.3 × 10-4) suggesting there is a relationship between ERCC1 expression and TILs, but this requires further investigation. CONCLUSION In conclusion, ERCC1 was identified as a potential biomarker of platinum response overall survival in HGSOC undergoing neoadjuvant HGSOC treatment.

Inhibition of extracellular matrix mediated TGF-β signalling suppresses endometrial cancer metastasis

Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-β signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-β pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-β signalling in non-glandular colonies. Importantly, alteration of TGF-β pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-β pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-β signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells.Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-β signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-β pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-β signalling in non-glandular colonies. Importantly, alteration of TGF-β pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-β pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-β signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells.