Does endocrine therapy for the treatment and prevention of breast cancer affect memory and cognition?

Oestrogen receptors have been identified in several areas of the brain important in cognitive performance, including the prefrontal cortex (active during short-term working memory), the hippocampus and related cortical areas (learning and storage of information) and the amygdala (involved in the modulation of memory consolidation). There is much debate as to whether or not a reduction in oestrogen levels results in a corresponding decline in cognitive processing. Arguments for an effect are based on findings from laboratory and hormone replacement studies and the pharmacological actions of breast cancer drugs. However, there are few clinical data substantiating the claim that endocrine therapies used in the treatment and prevention of breast cancer could affect cognition. This paper examines the main evidence associated with this claim and discusses the importance of examining such issues within randomised trials.     

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.     

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.     

Does hormone therapy counter the beneficial effects of physical activity on breast cancer risk in postmenopausal women?

Studies consistently demonstrate that physical activity is inversely associated with postmenopausal breast cancer. Whether this association is stronger among non-hormone users or former users of menopausal hormone therapy (HT) is of interest given the marked decline in HT use since 2002. The Women's Contraceptive and Reproductive Experiences Study, a population-based case-control study of invasive breast cancer, recruited white women and black women ages 35-64 years and collected histories of lifetime recreational physical activity and HT use including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT). Among postmenopausal women (1,908 cases, 2,013 control participants), breast cancer risk declined with increasing levels of lifetime physical activity among never HT users; among short-term HT users (fewer than 5 years); and among current ET users; P (trend) values ranged from 0.004 to 0.016. In contrast, physical activity had no significant association with risk among long-term and past HT users and among current EPT users. No statistical evidence of heterogeneity was demonstrated for duration or currency of HT use. Breast cancer risk decreases with increasing lifetime physical activity levels among postmenopausal women who have not used HT, have used HT for less than 5 years, or are current ET users, yet this study was unable to demonstrate statistically that HT use modifies the relationship between physical activity and breast cancer. With profound changes in HT use occurring since 2002, it will be important in future studies to learn whether or not any association between physical activity and breast cancer among former HT users is a function of time since last HT use.     

Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence

IntroductionTamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel “off-target” effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies.MethodA qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references.ResultsA total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC).ConclusionsWith increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.     

Does iron have a role in breast cancer?

Oestrogen and family history are two of the most important risk factors for breast cancer. However, these risk factors cannot explain the differences in the incidence and recurrence of breast cancer between premenopausal and postmenopausal women. In this paper I propose that, in premenopausal women, an iron deficiency caused by menstruation stabilises hypoxia inducible factor-1alpha, which increases the formation of vascular endothelial growth factor. This mechanism results in premenopausal women being more susceptible to angiogenesis and, consequently, leads to a high recurrence of breast cancer. Conversely, increased concentrations of iron in postmenopausal women, as a result of menstrual cessation, contribute to a high incidence of breast cancer via oxidative-stress pathways. Although the focus of this Personal View is on iron, this by no means negates the roles of other known risk factors in breast-cancer development. Characterisation of the role of iron in breast cancer could potentially benefit patients by decreasing recurrence and incidence and increasing overall survival.     

Endocrinology and hormone therapy in breast cancer: Selective oestrogen receptor modulators and downregulators for breast cancer – have they lost their way?

Although tamoxifen has been an effective treatment for breast cancer, several novel anti-oestrogen compounds have been developed with a reduced agonist profile on breast and gynaecological tissues. These include selective oestrogen receptor modulators (SERMs; both 'tamoxifen-like' and 'fixed-ring' SERMs) and selective oestrogen receptor downregulators (SERDs), although none has been proved superior in efficacy to tamoxifen in various advanced breast cancer trials. Thus, many have questioned whether a need for SERMs in breast cancer still exists, although chemoprevention remains a possible niche setting. In contrast, SERDs may have useful efficacy following aromatase inhibitors because of their unique mechanism of action, and clinical trials to determine their optimal use or sequence are ongoing.     

Does famotidine enhance tumor infiltrating lymphocytes in breast cancer? Results of a randomized prospective pilot study

Thirty patients with breast cancer were prospectively randomized into case and control groups receiving 40 mg famotidine preoperatively for 10-14 days and routine premedication, respectively. Surgical specimens were evaluated objectively for tumor infiltrating lymphocytes in the center and in the periphery of the tumor along with evaluation of metastatic lymph nodes for reactive changes. Ten famotidine-treated cases (67%) showed significant lymphocytic infiltration in the center compared to 4 controls (27%) (p = 0.03). Eleven cases (77%) had significant lymphocytic infiltration in the periphery (p = 0.03) compared to 5 controls (33%). Considering both sites, lymphocytic response was significant in 9 (60%) cases as opposed to only 3 (20%) controls (p = 0.03). This response did not correlate with the stage, grade of tumor or menopausal status of patients in either group. Seventy-eight percent (78%) of the cases showed significant reactive changes in the metastatic lymph nodes as compared to 22% in controls (p < 0.01). This study suggests that famotidine enhances tumor infiltrating lymphocytes in breast cancer and might have potential as an immunomodulator. A larger confirmatory study is suggested.     

Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer?

Low lignan status has been reported to be related to an elevated risk of breast cancer. Since lignan status is reduced by antibacterial medications, it is plausible to hypothesize that repeated use of antibiotics may also be a risk factor for breast cancer. History of treatment for urinary tract infection was studied for its prediction of breast cancer among 9,461 Finnish women 19-89 years of age and initially cancer-free. During a follow-up in 1973-1991, a total of 157 breast cancer cases were diagnosed. Women reporting previous or present medication for urinary tract infection at baseline showed an elevated breast cancer risk in comparison with other women. The age-adjusted relative risk was 1.34 (95% confidence interval (CI) = 0.98-1.83). The association was concentrated to women under 50 years of age. The relative risk for these women was 1.74 (95% CI 1.13-2.68), whereas it was 0.97 (95% CI 0.59-1.58) for older women. The relative risk in the younger age-group was 1.47 (95% CI 0.73-2.97) during the first 10 years of follow-up, and 1.93 (95% CI 1.11-3.37) for follow-up times longer than 10 years. These data suggest that premenopausal women using long-term medication for urinary tract infections show a possible elevated risk of future breast cancer. The results are, however, still inconclusive and the hypothesis needs to be tested by other studies.     

Does electron and proton therapy reduce the risk of radiation induced cancer after spinal irradiation for childhood medulloblastoma? A comparative treatment planning study

The aim of this treatment planning comparison study was to explore different spinal irradiation techniques with respect to the risk of late side-effects, particularly radiation-induced cancer. The radiotherapy techniques compared were conventional photon therapy, intensity modulated x-ray therapy (IMXT), conventional electron therapy, intensity/energy modulated electron therapy (IMET) and proton therapy (IMPT).

CT images for radiotherapy use from five children, median age 8 and diagnosed with medulloblastoma, were selected for this study. Target volumes and organs at risk were defined in 3-D. Treatment plans using conventional photon therapy, IMXT, conventional electron therapy, IMET and IMPT were set up. The probability of normal tissue complication (NTCP) and the risk of cancer induction were calculated using models with parameters-sets taken from published data for the general population; dose data were taken from dose volume histograms (DVH).

Similar dose distributions in the targets were achieved with all techniques but the absorbed doses in the organs-at-risk varied significantly between the different techniques. The NTCP models based on available data predicted very low probabilities for side-effects in all cases. However, the effective mean doses outside the target volumes, and thus the predicted risk of cancer induction, varied significantly between the techniques. The highest lifetime risk of secondary cancers was estimated for IMXT (30%). The lowest risk was found with IMPT (4%). The risks associated with conventional photon therapy, electron therapy and IMET were 20%, 21% and 15%, respectively.

This model study shows that spinal irradiation of young children with photon and electron techniques results in a substantial risk of radiation-induced secondary cancers. Multiple beam IMXT seems to be associated with a particularly high risk of secondary cancer induction. To minimise this risk, IMPT should be the treatment of choice. If proton therapy is not available, advanced electron therapy may provide a better alternative.     

Does hormone replacement therapy and use of oral contraceptives increase the risk of non-melanoma skin cancer?

Objective  

We aimed to examine whether use of hormone replacement therapy (HRT) and oral contraceptives (OC) affect the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in women.     

Does hyperbaric oxygen treatment have the potential to increase salivary flow rate and reduce xerostomia in previously irradiated head and neck cancer patients? A pilot study

Irradiated head and neck cancer survivors treated in the Hyperbaric Oxygen (HBO) Unit, Copenhagen University Hospital, spontaneously reported improvement of radiation-induced dry mouth feeling. The aim of this pilot study was to evaluate salivary flow rate and xerostomia before and after HBO in irradiated head and neck cancer patients. Eighty patients eligible for HBO treatment on the indication of prevention/treatment of osteoradionecrosis or soft tissue radiation injury were consecutively sampled, of whom 45 had hyposalivation (i.e. unstimulated whole saliva (UWS) flow rate <0.1ml/min), and 69 complained of xerostomia. UWS and stimulated whole saliva (SWS) were collected prior to and after 30 sessions of hyperbaric oxygen treatment over 6weeks. Xerostomia was assessed using the visual analogue scale (VAS). Each HBO session involved compression to 243kPa (2.4 ATA) for 90min while breathing 100% oxygen from a facemask or hood. There was a significant decrease in xerostomia (p<0.001) and slight increase in UWS (p<0.001) and SWS (p<0.001) flow rate, from before HBO as compared to after. Twenty-five of 45 patients with hyposalivation achieved an increased UWS flow rate after HBO. In 12 of these, the flow rates increased to levels not associated with hyposalivation. Patient-assessed improvement of xerostomia and slightly increased UWS and SWS secretion after HBO treatment suggest that HBO may have a beneficial effect on radiation-induced salivary gland damage.     

Primary endocrine therapy as a treatment for older women with operable breast cancer – A comparison of randomised controlled trial and cohort study findings

Introduction: One third of all breast cancers occur in women over the age of 70. Primary endocrine therapy (PET) is used in some women to minimise morbidity in a population with higher rates of comorbidity and frailty. In the UK up to 40% of women over 70 are treated with PET although there is a high rate of variability of practice between centres reflecting a lack of guidance about case selection.     

Surgical treatment and prognosis of breast cancer in elderly – A population-based study

BackgroundThe aim of this study was to investigate outcome of treatment in patients over 80 years of age with early breast cancer at the time of the diagnosis with special interest in surgical treatment.Materials and methodsBreast cancer patients older than 80 years of age, treated at the Breast Surgery Unit of Helsinki University Hospital in 2005–2010 were identified from electronic patient records. Patients were followed-up until the end of 2014. Patient and tumour characteristics, recurrences, co-morbidities and reasons for omission of surgery were collected from electronic patient records. Survival data was obtained from Finnish Cancer Registry.Results446 patients were eligible for the study: 401 (90%) received surgery. The median follow-up time was 52 months. In the entire study population, local and regional recurrences/disease progression were diagnosed in 16 (3.6%) and 6 (1.3%) patients, respectively. The five-year overall survival was 50.6% in the surgical treatment and only 15.2% in non-surgical treatment group, p < 0.001. Also, the five-year breast cancer specific survival was significantly better in the patients with surgery, 82.0%, but 56.0% in the patients without surgery, p < 0.001. There was no mortality related to the surgery, but 122 (30%) patients died within three years from surgery.ConclusionSurgical treatment rate was high. OS and BCSS were better in surgically treated elderly patients. Local and regional disease control was excellent, probably due to high rate of surgical treatment. Surgical treatment also seemed safe in this elderly patient population. However, surgical overtreatment was obvious in some patients.