Genetic and epigenetic alterations in breast cancer: what are the perspectives for clinical practice?

The worldwide incidence of breast cancer affects 1.2 million women each year. In contrast to the high occurrence of this malady, a decline in mortality is reported among industrialized countries. In this respect, both awareness campaigns and substantial progress achieved in therapy and diagnosis allowed for the enhancement of the survival rate in patients with breast cancer. Undoubtedly, oncology research programs played a relevant role in the improvement of therapeutics and diagnostics for breast cancer. Major strides were reported, especially over the last decade and a half, in better understanding molecular and cellular biology events involved in breast cancer pathogenesis and progression of the disease. However, therapeutic approaches for the treatment of patients with breast cancer need further improvement. Therapeutic interventions can chronically compromise both the state of health and quality of life of breast cancer survivors. In addition, current therapeutic approaches have not significantly improved the survival rate in patients with metastatic disease. On these grounds, it is necessary to develop more efficient therapeutics and diagnostic tools, which can improve the health and quality of life of breast cancer survivors and increase the survival rate in patients with metastatic disease. In this respect, the field of cancer research has placed a particular emphasis on the elucidation of genetic and epigenetic alterations that may lead to the pathogenesis of breast cancer and contribute to its progression.     

Are mu-opioid receptor polymorphisms important for clinical opioid therapy?

Mutations in the mu-opioid receptor--the primary site of action of opioid analgesics--are candidates for the variability of clinical opioid effects. This has been substantiated by recent advances in genetic research. A common mu-opioid receptor polymorphism was associated with higher demands for alfentanil or morphine for pain relief. It also decreased the potency of morphine for pupil constriction and experimental analgesia, but its molecular mechanisms are unclear. Another opioid receptor mutation greatly impaired receptor signalling in vitro, but is very rare. The accumulated evidence provides a solid basis for continuing research that should address the underlying molecular mechanisms and the role and benefits of OPRM1 genotyping for clinical pain therapy.     

Are climatic factors responsible for the process of oak decline in Poland?

Oak decline, a complex process leading to increased mortality of this species, has been observed in Europe for many years. Previous studies suggest that climate conditions, especially drought, may be one of the most important factors that trigger this phenomenon. The paper investigates the radial growth and wood anatomy features of pedunculate oak (Quercus robur) trees of various health status as well as their response to climate conditions. Wood samples including all annual increments were taken at two sites (western and central Poland, 15 trees each). Based on the crown defoliation level, three health groups (healthy, weakened and dead oaks) were distinguished. Cross-sections were prepared with sliding microtome and Cell P image analysis software was used for the measurements. Tree-ring width (TRW), earlywood vessels density (VDen) and non-weighted vessels diameter (VD) were determined and correlated with mean monthly values of temperature, precipitation, vapour pressure, and Palmer Drought Severity Index (PDSI). Radial increment and anatomical parameters were significantly higher for the healthy oaks than for the weakened and the dead trees. TRW showed smaller dependence on climate than analysed anatomical attributes. No obvious pattern of relationship was found between oak radial growth and climate regarding tree health status. Our results revealed that the drought has a weak impact on the process of oak decline on investigated sites in Poland.     

Steroid sulfatase inhibitors: promising new tools for breast cancer therapy?

Inhibition of aromatase is currently well-established as the major treatment option of hormone-dependent breast cancer in postmenopausal women. However, despite the effects of aromatase inhibitors in both early and metastatic breast cancer, endocrine resistance may cause relapses of the disease and progression of metastasis. Thus, driven by the success of manipulating the steroidogenic enzyme aromatase, several alternative enzymes involved in steroid synthesis and metabolism have recently been investigated as possible drug targets. One of the most promising targets is the steroid sulfatase (STS) which converts steroid sulfates like estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) to estrone (E1) and dehydroepiandrosterone (DHEA), respectively. Estrone and DHEA may thereafter be used for the synthesis of more potent estrogens and androgens that may eventually fuel hormone-sensitive breast cancer cells. The present review summarizes the biology behind steroid sulfatase and its inhibition, the currently available information derived from basic and early clinical trials in breast cancer patients, as well as ongoing research. Article from the Special Issue on Targeted Inhibitors.     

Is preoperative core biopsy accurate in determining the hormone receptor status in women with invasive breast cancer?

Background

The objective of this study was to determine the concordance rate between core needle biopsy (CNB) and surgical excision of invasive breast cancer regarding the oestrogen receptor (ER) and Progesterone receptor (PgR) status as determined by Immunohistochemistry (IHC).

Methods

Hormone receptor status was established using IHC (using quickscore system 0–8) on preoperative CNB and subsequent surgical excision in 93 patients with invasive breast cancer. Results were compared taking into account tumour's size, grade, and patient's age.

Results

The ER concordance rate between CNB and surgical excisions was 95%. The PgR concordance rate was 89%. This shows that CNB has a sensitivity of 97% for ER and 95% for PgR.There is a positive correlation of ER and PgR between CNB and surgical excision (p < 0.000001). There was no significant difference in the number of core biopsies between concordant and discordant cases.

Conclusion

Preoperative core biopsy is highly sensitive for the IHC detection of ER and PgR in invasive breast cancer. The concordance rate is higher for ER than PgR, which could be due to the fact that ER is more homogeneously distributed.

     

Should the management of radiation therapy for breast cancer be standardized? Results of a survey on current French practices in breast radiotherapy

BackgroundBreast cancer is the most frequent cancer in women in France. Its management has evolved considerably in recent years with a focus on reducing iatrogenic toxicity. The radiotherapy indications are validated in multidisciplinary consultation meetings; however, questions remain outstanding, particularly regarding hypofractionated radiotherapy, partial breast irradiation, and irradiation of the internal mammary chain and axillary lymph node area.Materials and methodsAn online survey was sent to 47 heads of radiotherapy departments in France. The survey consisted of 22 questions concerning indications for irradiation of the supraclavicular, internal mammary and axillary lymph node areas; irradiation techniques and modalities; prescribed doses; and fractionation.ResultsTwenty-four out of 47 centers responded (response rate of 51%). This survey demonstrated a wide variation in the prescribed dose regimen, monoisocentric radiotherapy, and indications of irradiation of the lymph node areas.ConclusionThis survey provides insight into the current radiotherapy practice for breast cancer in France. It shows the need to standardize practices.     

The fight against tamoxifen resistance in breast cancer therapy: a new target in the battle?

Tamoxifen is one of the most successful and widely used chemopreventive agents ever, and is an effective therapeutic agent for inhibiting growth of hormone receptor positive breast cancers. Tamoxifen and some of its metabolites bind to estrogen receptors and allow subsequent DNA binding at estrogen responsive genes, blocking some estrogenic signals while maintaining others, depending on the tissue. When used therapeutically for up to five years, cases of tamoxifen resistance appear, requiring alternative therapies. One recent proposal uniquely targets a zinc finger of the DNA binding domain of estrogen receptors, rather than the ligand binding domain, to circumvent resistance. In light of the most recent clinical data, however, it is now clear that aromatase inhibitors are the preferred first line therapy for all stages of breast cancer in post-menopausal women, whether they have had previous tamoxifen exposure or resistance.     

Does the modern urbanized sleeping habitat pose a breast cancer risk?

Due to its disruptive effects on circadian rhythms and sleep deprivation at night, shiftworking is currently recognized as a risk factor for breast cancer (BC). As revealed by the present analysis based on a comparative case-control study of 1679 women, exposure to light-at-night (LAN) in the "sleeping habitat" is significantly associated with BC risk (odds ratio [OR]?=?1.220, 95% confidence interval [CI]?=?1.118-1.311; p?相似文献   

Breast reduction surgery and breast cancer risk: does reduction mammaplasty have a role in primary prevention strategies for women at high risk of breast cancer?

Prophylactic bilateral mastectomy has been demonstrated to reduce breast cancer incidence in women with a high inherited susceptibility to breast cancer. For the majority of high-risk women, however, bilateral prophylactic mastectomy is not an acceptable option for primary prevention of breast cancer. Several epidemiological follow-up studies have indicated that there may be a substantial reduction in breast cancer risk among women who have undergone breast reduction surgery. The authors reviewed the evidence from these studies, with emphasis on the problems inherent in interpreting the results of nonexperimental studies of elective medical procedures. Although such observational studies cannot demonstrate definitively that reduction mammaplasty reduces the risk of breast cancer, the evidence from these studies is sufficiently strong to warrant the evaluation of breast reduction surgery as an option for primary prevention in clinical studies of women at increased risk of breast cancer. The availability of a more acceptable surgical option for primary prevention of breast cancer could increase the number of women willing to choose risk reduction surgery and thus may result in an overall reduction in breast cancer mortality among high-risk women.     

What is the evidence for the clinical value of SBRT in cancer of the cervix?

AimThe aim of this review is to describe and analyze indications and results of the use of SBRT in uterine cervix cancer, reviewing articles published from January 2010 up to August 2017, for any one of the four indications listed:

• 1Patient refusal or anatomic impediments to interstitial or intracavitary brachytherapy (BCT), i.e. SBRT as an “alternative” for BCT;
• 2Patients with voluminous tumors, or asymmetric tumors where BCT alone would not achieve curative doses, i.e. SBRT as a primary adjunct to BCT;
• 3Pelvic and para aortic adenopathy where SBRT could be used as a boost, i.e. SBRT as a primary adjunct to external beam pelvic radiotherapy;
• 4Small volume recurrences (postoperative or post radiotherapy), i.e. SBRT for salvage.

BackgroundCervix cancer standard treatment involves pelvic irradiation and chemotherapy, recent advances in irradiation techniques might offer new possible approaches.Material and methodsSystematic review of the English language literature about Cervix cancer, SBRT, published from January 2010 to January 2018 identified through a database search of PubMed, and Ovid MEDLINE, using pre-defined search phrases.ResultsThe results in the literature, in general, demonstrate rather weak efficacy of SBRT. In this review, we did not find strong evidence to recommend routine SBRT as a primary treatment for cervico-uterine cancers, i.e. as a replacement for BCT; in highly selected cases it might be considered useful as salvage therapy for relapsed cervix cancer.ConclusionThe existing data to not warrant recommending SBRT for the definitive treatment of cervix cancer, but may have some value in the recurrent/relapsed setting.     

Are lipid phase transitions responsible for chilling damage in human platelets?

In previous studies we have proposed that the well-known chilling-induced activation of human blood platelets can be ascribed at least in part to a thermotropic phase transition in membrane lipids. The evidence that this is the case is reviewed and amplified in this review, followed by an examination of the available physical data concerning phase transitions in lipid mixtures that mimic the mixture found in platelet membranes. Assuming complete mixing at all temperatures and equal contributions of the members of the mixture to the phase transition, the lipid mixture found in platelets should give values for Tm ranging from about 1 degrees C to about 16 degrees C, depending on the isomers present in the mixture. (The former value is not in agreement with the observed Tm, but the latter is in excellent agreement.) However, examination of the phase diagram for a binary pair of lipids found in platelet membranes shows that ideal mixing almost certainly does not occur; instead of a linear phase diagram, a convex one was obtained. This shape for the phase diagram, which would displace Tm to an unexpectedly elevated temperature, is in agreement with previously published phase diagrams for mixtures of this type. The prediction, based on thermodynamic properties of lipids found in the platelets, is that Tm will be displaced upward in more complex mixtures of the composition found in platelets, a prediction that requires experimental testing.     

Is there a real risk of radiation-induced breast cancer for postmenopausal women?

The risk of radiation-induced breast cancer decreases with increasing age at exposure. Thus, for calculating the individual risk for a patient undergoing mammography, age-related risk coefficients need to be used. In this report, the results of epidemiological studies on risks of radiation-induced breast cancer are reviewed indicating that the available data do not show the risk to be enhanced for women exposed at the age of 55 years or older. This lack of evidence is reflected by the fact that the risk coefficients recommended by national and international advisory bodies differ by a factor of 10 or more for age at exposure of 50–60 years or older. A hypothesis is proposed indicating that the risk of radiation-induced breast cancer might decrease considerably at the time of menopause. The hypothesis is based on the following line of arguments: (1) evidence has accumulated from molecular genetic studies indicating that the development of colorectal cancer requires a cascade of subsequent mutations consisting of at least seven genetic events. (2) For colorectal cancer, the annual rates of incidence and mortality increase with age to the power of 5–6. Thus, the number of mutation steps (minus 1) is approximately reflected by the power of age dependence. (3) For western populations, the incidence and mortality of breast cancer up to the age of about 50 years increase with age to the power of about 6, indicating that a similar number of genetic events might be involved in development of breast cancer as has been identified for colorectal cancer. (4) For women aged 50 years or older, breast cancer occurs at an annual rate that is about proportional to age or age squared. This may mean that after menopause, the processes in the multistep mutation cascade leading to breast cancer are slowed down by a factor of about 4 or more. (5) The constant relative risk model of radiation carcinogenesis implies for solid cancers that radiation acts by inducing additional mutations in the earlier steps of the multistep cascade. It is suggested that the break-point in the age-specific annual rate of breast cancer incidence at menopause is associated with a corresponding drop in radiation sensitivity with respect to induction of breast cancer. Received: 8 January 2001 / Accepted: 20 March 2001     

Are the short-photoperiod-induced decreases in serum prolactin responsible for the seasonal changes in energy balance in Syrian and Siberian hamsters?

Serum prolactin (PRL) decreases in Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus sungorus) hamsters following short-photoperiod exposure. Both species also exhibit short-photoperiod-induced changes in body and lipid mass, but in opposite directions; Syrian hamsters increase and Siberian hamsters decrease their body weight, changes reflected nearly exclusively in their carcass lipid content. The purpose of these experiments was to determine whether the photoperiod-induced changes in PRL were responsible for the seasonal changes in energy balance in Syrian and Siberian hamsters by using the strategy of experimentally producing serum PRL levels opposite to those normally associated with the photoperiod in which the animals were housed. In long photoperiods serum PRL was reduced to short-day levels by subcutaneous (s.c.) CB-154 (bromoergocryptine, a dopamine agonist) injections. In short photoperiods, serum PRL was elevated to long-day levels in Syrian hamsters by ectopic pituitary explants, and in Siberian hamsters, serum PRL was elevated by chronic s.c. infusions of ovine PRL (oPRL). In both species, manipulations of serum PRL did not affect food intake, carcass composition, or the wet weight of various white and brown adipose tissue pads (WAT and BAT, respectively). Body weight increased in CB-154-treated Syrian hamsters and decreased in Siberian hamsters, an effect partially reversed by coadministration of oPRL in Syrian, but not Siberian, hamsters. Thus, lowering serum PRL to short-day levels in long-day-housed hamsters of both species mimicked the directional change in body weight appropriate for each species when they are exposed to short days. This effect of CB-154 on body weight may be a result of some as yet unidentified effect of dopaminergic stimulation on overall growth since 1) these changes in body weight were not reflected as changes in lipid mass, as occurs naturally following short-day exposure for each species, and 2) neither species exhibited a reciprocal change in body weight when serum PRL was experimentally elevated in short days. Alternatively, it may be that once the energetic responses to short-day exposure have been fully expressed, the ability of PRL to stimulate the target sites of action for PRL for these responses may be decreased. BAT protein content, cytochrome oxidase activity (measures of metabolic growth of this tissue), and retroperitoneal total and specific lipoprotein lipase (LPL) activities were increased by CB-154 treatment in Syrian hamsters.(ABSTRACT TRUNCATED AT 400 WORDS)