Breast cancer stem cells: tools and models to rely on

There is increasing evidence for the "cancer stem cell (CSC) hypothesis", which holds that cancers are driven by a cellular component that has stem cell properties, including self-renewal, tumorigenicity and multi-lineage differentiation capacity. Researchers and oncologists see in this model an explanation as to why cancer may be so difficult to cure, as well as a promising ground for novel therapeutic strategies. Given the specific stem cell features of self-renewal and differentiation, which drive tumorigenesis and contribute to cellular heterogeneity, each marker and assay designed to isolate and characterize CSCs has to be functionally validated. In this review, we survey tools and markers available or promising to identify breast CSCs. We review the main models used to study breast CSCs and how they challenge the CSC hypothesis.     

Patient reported outcome measures (PROMs) following forward planned field-in field IMRT: Results from the Cambridge Breast IMRT trial

Background

The use of intensity-modulated radiotherapy (IMRT) in breast cancer reduces clinician-assessed breast tissue toxicity including fibrosis, telangectasia and sub-optimal cosmesis. Patient reported outcome measures (PROMs) are also important as they provide the patient’s perspective. This longitudinal study reports on (a) the effect of forward planned field-in-field IMRT (∼simple IMRT) on PROMs compared to standard RT at 5 years after RT, (b) factors affecting PROMs at 5 years after RT and (c) the trend of PROMs over 5 years of follow up.

Methods

PROMs were assessed at baseline (pre-RT), 6, 24 and 60 months after completion of RT using global health (EORTC QLQ C30) and 4 breast symptom questions (BR23). Also, 4 breast RT-specific questions were included at 6, 24 and 60 months: change in skin appearance, firmness to touch, reduction in breast size and overall change in breast appearance since RT. The benefits of simple IMRT over standard RT at 5 years after RT were assessed using standard t-test for global health and logistic regression analysis for breast symptom questions and breast RT-specific questions. Clinical factors affecting PROMs at 5 years were investigated using a multivariate analysis. A repeated mixed model was applied to explore the trend over time for each of PROMs.

Results

(89%) 727/815, 84%, 81% and 61% patients completed questionnaires at baseline, 6, 24 and 60 months respectively. Patients reported worse toxicity for all four BR23 breast symptoms at 6 months, which then improved over time (p < 0.0001). They also reported improvement in skin appearance and breast hardness over time (p < 0.0001), with no significant change for breast shrinkage (p = 0.47) and overall breast appearance (p = 0.13). At 5 years, PROMs assessments did not demonstrate a benefit for simple IMRT over standard radiotherapy. Large breast volume, young age, baseline surgical cosmesis and post-operative infection were the most important variables to affect PROMs.

Conclusions

This study was unable to demonstrate the benefits of IMRT on PROMs at 5 years. PROMs are influenced by non-radiotherapy factors and surgical factors should be optimised to improve patients’ outcome. Only a small proportion of patients report moderate–severe breast changes post radiotherapy, with most PROMs improving over time. The difference in clinician assessment and PROMs outcome requires further investigation.     

Breast cancer assessment tools and optimizing adjuvant therapy

Recommendation of systemic adjuvant therapy and choice of optimal agents for early-stage breast cancer remains a challenge. Adjuvant therapy is indicated on the assumption of residual micrometastatic disease. Adjuvant assessment tools for prognosis and prediction of treatment benefit, including Adjuvant! Online, the St Gallen Consensus, Oncotype DX(?) and MammaPrint(?), aid clinical decision making. However, all of these tools have limitations that must be considered in their judicious application. Clinicopathological based tools are critically dependent on accurate, standardized measurement of parameters. Multigene tools are appealing for their objectivity and reproducibility, particularly regarding analysis of proliferation, but these approaches still overlook the biological heterogeneity within tumors evidenced by distinct cell subpopulations with different genomic patterns and function. The greatest treatment challenge remains for patients assessed as intermediate risk of relapse, a problem not overcome by multigene tools. Remarkable diversity in breast cancer dictates that adjuvant management must be biologically driven. Future identification of predictive biomarkers for specific chemotherapy sensitivity may allow targeted use of available agents, including anthracyclines, taxanes and DNA damaging agents. The presence of drug targets and targetable signaling pathways, rather than molecularly defined subgroups, may ultimately drive treatment decisions.     

VMAT和IMRT技术在乳腺癌根治术后放疗中的剂量学比较?

目的：比较容积旋转调强治疗( VMAT)和固定野调强治疗( IMRT)两种技术在乳腺癌根治术后放疗中剂量学的差异。方法：选择10例右侧根治术后乳腺癌放疗的病人,使用Oncentra4．3计划系统,快速容积旋转调强(VMAT)起始角度为55°,结束角度为215°,双弧;固定野调强技术(IMRT)采用六野照射,同一病人两种计划的中心点和优化目标条件均一样。靶区处方为50Gy/25次。评估两种计划靶区的适形度指数和均匀性指数,以及正常器官如患侧肺,正常肺,对侧乳腺,心脏等器官的剂量;机器跳数,治疗时间。结果： VMAT组的靶区均匀性指数(HI)好于IMRT(低29．9%),分别为0．129±0．021,0．184±0．04,P=0．000。适形度指数CI差别不大,差异没有统计学意义。 VMAT组的患侧肺,正常肺的V5,V20,以及平均剂量均低于IMRT组。且前者靶区内外的剂量曲线更为接近,低剂量区域的受照面积较IMRT更少,出射总跳数减少了28．5%( P=0．000),治疗时间缩短了80%(P=0．000)。结论：VMAT技术在术后乳腺癌的治疗应用上,相比IMRT技术而言,能够明显降低患侧肺及其他危及器官的受量。同时照射时间,跳数总数也明显低于IMRT,缩短了病人的治疗时间,减小了因时间过长病人移动带来的误差,降低了加速器的损耗率,提高了机器工作效率。     

Breast cancer: new radiation treatment options

Conventional radiotherapeutic treatment for early and advanced breast cancer has been based on broad-field radiation treatment principles that date back several decades. Although these strategies have been successful, newer techniques now offer the ability to incorporate improved target imaging, dosimetric planning, and treatment delivery into the treatment design. These newer techniques include accelerated partial-breast irradiation and hypofractionated whole-breast irradiation for early-stage breast cancer, and intensity-modulated radiotherapy (IMRT) for both early and advanced breast cancer. Accelerated partial-breast irradiation and hypofractionated whole-breast radiotherapy are treatment approaches that promise both reduced overall treatment times and the potential for increased use of breast-conservation therapy. IMRT offers unparalleled dose homogeneity and conformality that enables dose reduction to normal structures with the potential to reduce treatment toxicity and improve cosmesis. Based on the published literature, an increasing number of treatment facilities are offering treatment with these techniques. However, further clinical study remains important to thoroughly define the appropriate clinical setting, patient selection criteria, and limitations for each of these innovative treatment approaches.     

Pharmacogenetics and pharmacogenomics as new tools to optimise cancer chemotherapy

Pharmacogenetics takes into account the individual variability of the genome and its relationships with drug activity. Numerous gene polymorphisms occurring at the level of drug metabolising enzymes, drug transporters or drug targets have been identified; they may be responsible for an alteration of the phenotype, and of individual changes in drug efficacy and/or toxicity. Pharmacogenomics takes into account the genetic alterations present in tumours and their role in drug activity. It may be possible to establish correlations between the activity of a drug and the level of expression of tumour genes, and thus select the most appropriate drugs to prescribe for the treatment of individual tumours. Pharmacogenetics and pharmacogenomics are acting synergistically for the personalisation of treatments, on the basis of the constitutive singularity of patients and of the molecular characteristics of tumours.     

From IMRT to IGRT: frontierland or neverland?

The recent enthusiasm for real-time image guidance in radiotherapy (IGRT) is in part due to the commercial availability of advanced on-line imaging technologies. Perhaps more important than its potential to improve conventional radiotherapy, IGRT may lead to a paradigm shift in facilitating hypo-fractionated or single-dose treatment. However, there are uncertainty regarding features and approaches of competing IGRT systems and as to whether a sub-set of the features of an ideal IGRT system would suffice for specific disease sites and clinical applications. Clinical studies are necessary for the quantification of benefit needed for evidence-based medicine.     

Breast cancer: new trends of clinical research

In breast physiopathology, in spite of the crop of information and clinical studies, a number of questions are still unsolved. The adequacy of research sources and the transmission of information to clinical practice through consistent and validated efficacy evidences are required to ensure the treatment quality. In this article the different specialist approaches and the main themes debated in the interdisciplinary approach to breast cancer are considered: the genetical risk factors, the role of diagnostic imaging, the mapping and assessment of sentinel lymph node, the role of nodal radiation therapy following mastectomy.     

Breast cancer chemoprevention – a vision not yet realized

Despite recent advances in the surgical and medical treatment of breast cancer, the number of patients dying from the disease is still high. In addition to improvements of early diagnosis and treatment, the overall mortality of breast cancer could be reduced by means of preventive intervention in both women with particularly normal and with high risk. Preventing the potentially deadly disease is presumably more effective than treatment, for life quality issues as well as for the economic perspective. Chemoprevention though is still a research field with results from large prevention trials being discussed controversially. For women with a defined increased risk for breast cancer, tamoxifen may be a choice for chemoprevention, balancing carefully benefits against risks. With promising results in adjuvant settings, aromatase inhibitors may deliver better prevention treatment options in the future, nevertheless, more research is needed to reliably predict risk on an individual basis in the future.     

Screening for ovarian cancer: old tools, new lessons

The early detection of ovarian cancer represents a clinical objective with an enormous potential for a meaningful improvement in our ability to treat and cure afflicted patients. The magnitude of this potential is matched by the challenges associated with attaining it. In addition to the well noted aspects of ovarian cancer which have thus far precluded the development a effective screening strategies, recent work regarding the differential pathogenesis and origins of the various histological subtypes of epithelial ovarian cancer have further revealed the challenges ahead. These findings are reviewed here with a particular focus on reports describing the early development of high-grade serous carcinomas, the most prevalent and aggressive disease subtype. The unique set of difficulties associated with the early detection of these tumors is discussed in depth. An update on findings stemming from several large randomized screening trials is provided. While the current state of ovarian cancer screening remains characterized by unmet needs, the ongoing evaluation of those needs is providing a strong basis for future advancement. This advancement will rely upon the refined application of currently available diagnostic tools based on lessons well learned.     

EMT: a new vision of hypoxia promoting cancer progression

A hypoxic microenvironment plays a critical role in the development and progression of tumors. The epithelial to mesenchymal transition (EMT) is a process by which epithelial cells lose their polarity and are converted to a mesenchymal phenotype, which is regarded as a critical event in morphogenetic changes during embryonic development, wound healing, and cancer metastasis. Recent advances in our understanding of the molecular pathways that govern the association of hypoxia with malignant tumors point to the epithelial to mesenchymal transition (EMT). The hypoxic microenvironment common to cancer cells emerges as an important factor in the induction of a pathological EMT, which is a key link in cancer progression. This review presents the potential molecular mechanisms underlying the hypoxia/HIF-dependent regulation of the EMT in cancer.     

Epidemiology of pancreatic cancer: New version,new vision

Pancreatic cancer(PC) is a devastating malignancy with an extremely high mortality rate and poses significant challenges to healthcare systems worldwide. The prevalence of PC risk factors spiked over the years, leading to a global increase in PC incidence rates. The contribution of different risk factors, however, varied from region to region due to genetic predisposition, environmental, social, and political factors underlying disease prevalence in addition to public health strategies. This com...