In silico design of small peptide-based Hsp90 inhibitor: A novel anticancer agent

Background

Breast cancer is a common disease found among women and has been a serious issue for last two decades. Although various kinds of heat shock proteins (Hsp’s) have strong implications in cancer, heat shock protein 90 alpha (Hsp90α) has attracted highest attention for the cause and therapy of breast cancer. It regulates approximately 200 numbers of proteins known as client proteins including large number of oncoproteins found to be upregulated in many cancer cells. Therefore, inhibition of Hsp90α is a common therapeutic approach pursued in many cancers. However, Hsp90α inhibitors both natural and chemical, reported so far are plagued with problems related to toxicity, bioavailability and solubility including geldanamycin, the most common Hsp90α inhibitor. Therefore, search for a suitable Hsp90α inhibitor is an urgent need.

Hypothesis

Here we hypothesize that Hsp organizing protein (HOP) helps in the interaction of Hsp90α with Hsp70, which is the key to appropriate chaperonin function of Hsp90α and therefore, inhibiting such interaction might lead to the disruption of Hsp90α-client protein complex, which in turn destabilize and degrade client proteins. We further hypothesize that considering the residues involved in the reaction we can design novel peptide based Hsp90α inhibitor.

Experimental design

In our present in silico investigation, we hypothesized that the chaperone function of Hsp90α requires the complex formation with HOP and co-chaperones Hsp70, Hsp40. We performed the docking interaction between Hsp90α and HOP. Based on the key residues involved in the interaction between Hsp90α and HOP, we designed ten peptides having twelve amino acids each. We docked the designed peptides with Hsp90α using docking software Hex 6.1 and the peptide with the highest binding energy value was identified. Using the online FOLDAMYLOID program, we assessed their amyloidogenic propensity. Amylodegenic properties were also considered and based on that five different peptides were again redesigned. Several modifications incorporated onto the peptide led to the design of five different peptides.

Results

The peptide with the lowest amyloidogenic properties and highest binding energy for Hsp90α was the criteria laid for selection as an Hsp90α-inhibitor. Its potential to bind Hsp90α and disrupt Hsp90α–HOP complex was subsequently investigated using both wild as well as mutant p53 as a client protein.

Conclusion

The predicted binding energy values showed that our designed novel peptide demonstrated strong binding affinity for Hsp90α. Subsequently, the binding affinity of Hsp90α for mutant p53 was shown to be reduced substantially indicating a strong inhibitory potential of the designed peptide PEP73 (INSAYKLKYARG) for Hsp90α.     

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet,Cancer and Health’ prospective cohort

Objectives

The association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.

Study design

Female participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.

Main outcome measure

Breast cancer specific mortality.

Results

Of the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)

Conclusions

HRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.     

Evaluation of a virtual dialogue method for breast cancer patient education

Objective

Virtual dialogue—a voice-activated, interactive computer model that enables a user to have an individual virtual conversation with a real person—was evaluated as a method to educate women about breast cancer. Virtual dialogues with breast cancer experts were developed and used in a field study by women with and without the disease to assess the method's effectiveness.

Methods

In a clinical setting, subjects engaged in one-on-one virtual dialogues with an oncologist and a breast surgeon, and completed automated pre–post instruments developed to measure the feasibility of the method, and subjects’ knowledge gain and acceptance of the method.

Results

Seventy women, 39 with breast cancer and 31 without the disease, participated. The data demonstrated the feasibility and acceptance of the method, and significant learning gain across all subjects.

Conclusion

Virtual dialogues with knowledgeable health professionals can be a new and effective method for educating women about breast cancer.

Practice implications

Virtual dialogues may systematically comfort patients while providing them with comprehensive and reliable basic information about breast cancer. The method may also give health care providers more time to address their patients’ specific concerns.     

Targeted therapy and breast cancer: State of the art

Context

Scientific advances in molecular biology and understanding of oncogenesis have lead to anticancer molecular targeted therapies. They encompass monoclonal antibodies binding to active membrane epitopes and small molecules interfering with enzymatic reactions essential to cancer cell survival (oncogene addiction). These pathways may be optimal targets. Clinical benefits achieved using these targeted agents have been outstanding both in localized and metastatic disease.

Method

We conducted a survey of literature analyzing activity and safety of targeted agents approved by FDA and/or FDA for the treatment of patients with breast cancer: anti-HER2 and antiangiogenic agents.

Results

Activity and main toxicities of these targeted agents are described according to signaling pathway targeted as well as stage of breast cancer.

Conclusions

Availability of these targeted therapies has indeed transformed the outcome of subgroups of breast cancer to the expense of acceptable and manageable side effects, as compared to classical cytotoxics to which they are nevertheless combined.     

Identifying a C-terminal ATP binding sites-based novel Hsp90-Inhibitor in silico: A plausible therapeutic approach in Alzheimer’s disease

Background

Alzheimer’s disease (AD) is a progressive brain disorder, which gradually and irreversibly destroys the intellectual and cognitive abilities of the brain. Heat shock protein 90 (Hsp90α) is a molecular chaperone which was found to regulate the function of number of client proteins including tau that is involved in the cause of the AD. Inhibition of Hsp90α by C-Terminal domain (CTD) ATP binding-site blockage might be used as an effective treatment strategy against the disease via degradation of tau proteins that are involved in the progression of the disease. Till date, a variety of drugs have been identified as Hsp90α inhibitors, which include Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone. However, which drug among the four binds to the CTD ATP binding site strongly and what are the specific residue responsible for such binding, have not been reported so far.

Hypothesis

We hypothesize that binding site for ATP of Hsp90α CTD contains multiple ATP binding sites. We also hypothesize that a drug which can bind to the ATP binding site of CTD strongly can inhibit Hsp90α function which is in turn redirects towards the proteasomal degradation of diseased client protein like tau in AD. Such inhibition will find a novel therapeutic approach in the treatment of AD.

Experimental design

The identification of ATP binding site of Hsp90α CTD was done using various software tools like Hex 6.3, CastP, protein Hydrophobicity plots, ATPint and LigPlot+ v.1.4.5. Docking experiments were conducted between Hsp90αCTD and its inhibitors at these ATP binding site using the Autodock 4.0. The docking energies were further compared to obtain the most effective Hsp90α inhibitor of CTD.

Results

From our experiments, Leucine (Leu) 665, Leu 666 and Leu 694 were predicted to be located in CTD ATP binding site. Furthermore, docking studies were performed of various Hsp90α inhibitors like Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone with the previously recognized ATP binding residues of CTD i.e. Leu 665, Leu 666 and Leu 694. The docking results of Derrubone showed the highest binding energy at all the three sites of ATP interaction. Additionally, Derrubone showed the best binding energy at Leu 666 (−7.53 kcal/mol) compared to Leu 665 (−7.20 kcal/mol) and Leu 694 (−6.67 kcal/mol).

Conclusion

Based on our findings, we propose that the recognized sites i.e. Leu665, Leu 666 and Leu694 could possibly be the binding sites of Hsp90α CTD for ATP and the Hsp90 inhibitors. It was predicted that Derrubone could bind with CTD of Hsp90α strongly and resulted tau protein degradation which might be considered to be a therapeutic approach in AD.     

Safety of herbal medicinal products in women with breast cancer

Objective

To review and summarise current evidence on the efficacy and safety of herbal medicinal products for the relief of hot flushes in women with previous breast cancer.

Methods

A literature search was conducted in the databases of Medline, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), PSYCHINFO, AMED (Allied and Complementary Medicine), NCCAM (The National Centre for Complementary and Alternative Medicine).

Results

Black cohosh and phytoestrogens have received the most research attention but there is currently insufficient evidence to recommend either for relief of flushes. Black cohosh use appears safe in women with previous breast cancer. Opposing advice has been given regarding the safety of dietary phytoestrogen use for women with previous breast cancer, but there is emerging data that soyfood phytoestrogen intake may have a beneficial effect on tumour recurrence.

Conclusions

The majority of studies, regarding the efficacy of herbal treatments for hot flushes, have not been conducted in women with breast cancer and many are of short duration. Increased pharmacovigilance practices for herbal medicines are required with initiatives to stimulate reporting of suspected adverse reactions.     

"Seeing is believing, and believing is seeing": an exploration of the meaning and impact of women's mental images of their breast cancer and their potential origins

Objective

To explore the nature, meaning and perceived origin of women's mental images of their breast cancer.

Methods

Fifteen women, who had completed treatment for primary breast cancer, participated in this qualitative in-depth interview study. Data were analysed using a constant comparative technique within the “Framework” method.

Results

Almost all women had a mental image of their cancer. Images reflected their beliefs about their illness (its appearance, character and dangerousness) and appeared to be related to a number of fears and concerns. The origin of images was uncertain but appeared to be influenced by scan images, verbal metaphors presented by health professionals, and previous beliefs held about cancer. Some women used metaphors presented to infer properties of the cancer that may have been unintended by the health professional.

Conclusion

Women may have mental images of their breast cancer that are associated with hope, reassurance, anxiety, despair, or views about the future. Further longitudinal research is required to establish the origin and importance of these images.

Practice implications

Health professionals may find that exploring women's mental images of their cancer is a helpful way of identifying potential misunderstandings about their illness.     

Testing whether decision aids introduce cognitive biases: Results of a randomized trial

Objective

Women at high risk of breast cancer face a difficult decision whether to take medications like tamoxifen to prevent a first breast cancer diagnosis. Decision aids (DAs) offer a promising method of helping them make this decision. But concern lingers that DAs might introduce cognitive biases.

Methods

We recruited 663 women at high risk of breast cancer and presented them with a DA designed to experimentally test potential methods of identifying and reducing cognitive biases that could influence this decision, by varying specific aspects of the DA across participants in a factorial design.

Results

Participants were susceptible to a cognitive bias – an order effect – such that those who learned first about the risks of tamoxifen thought more favorably of the drug than women who learned first about the benefits. This order effect was eliminated among women who received additional information about competing health risks.

Conclusion

We discovered that the order of risk/benefit information influenced women's perceptions of tamoxifen. This bias was eliminated by providing contextual information about competing health risks.

Practice implications

We have demonstrated the feasibility of using factorial experimental designs to test whether DAs introduce cognitive biases, and whether specific elements of DAs can reduce such biases.     

The Asian Menopause Survey: Knowledge,perceptions, hormone treatment and sexual function

Objective

To provide current insights into the opinions, attitudes, and knowledge of menopausal women in Asia regarding menopause and hormone replacement therapy (HRT).

Study design

Cross-sectional.

Main outcome measures

Between January 2006 and February 2006, 1000 postmenopausal women from China, Malaysia, Taiwan, Thailand and Hong Kong were interviewed to determine postmenopausal symptoms, HRT use and knowledge, breast discomfort and knowledge of breast cancer risks, and sexual function.

Results

Almost all women reported experiencing postmenopausal symptoms. Sleeplessness (42%) was reported as the main reason for seeking treatment. On average, 54% of women were aware of HRT, despite the fact that most (38%) were unable to mention any associated benefits. Most women had used natural or herbal treatments (37%) for the alleviation of menopausal symptoms. Only 19% had received HRT. 27% of respondents reported having breast discomfort, while 70% reported performing self-breast examinations. 53% of women had never received a mammogram, despite breast cancer concern (50%). 24% of women described HRT as being a risk factor for breast cancer. Most women and their partners reported no reductions in sexual function (66 and 51%, respectively), while 90% of respondents did not seek treatment for reduced sexual function. In the event of sexual dysfunction, 33% of women replied that they would be willing to seek treatment.

Conclusions

Many Asian women experience postmenopausal symptoms that are often left untreated (due to the acceptance of menopause as a natural process) or treated with herbal/natural remedies. There was a general lack of knowledge among these women regarding treatment options, HRT, and possible risks associated with HRT. A more concerted effort should be made to better disseminate information regarding the pathogenesis and risk factors associated with breast cancer, menopause, and menopausal symptoms to Asian women.     

Influence of insulin resistance on adiponectin receptor expression in breast cancer

Objective

Adipositas and insulin resistance are modifiable risk factors for breast cancer. Adiponectin seems to be an important linkage of these associations. In this study, we investigated the relationship between intratumoral adiponectin receptor expression and insulin resistance as well as intratumoral insulin/IGF receptor expression in breast cancer specimen.

Methods

Breast cancer tissue and fasting serum were collected from 26 female patients. After microdissection of frozen samples, RNA was isolated and expression of insulin receptor, IGFR1, IGFR2, AdipoR1 and AdipoR2 was measured on mRNA level by means of real time RT-PCR. Fasting insulin, glucose and c-peptide serum levels were analysed by ELISA. Insulin resistance was calculated using the HOMA model.

Results

We were able to confirm AdipoR1 and AdipoR2 expression, respectively, in breast cancer specimen. Actually, neither insulin serum level nor whole-body insulin resistance showed any effect on insulin/IGF or adiponectin receptor expression in breast cancer. A strong positive correlation between insulin as well as IGF1 receptor and AdipoR1, but not AdipoR2, expression could be observed. Interestingly, AdipoR2 expression significantly correlated with vascular and lymphovascular invasion of breast cancer.

Conclusion

We propose a close relationship between the intratumoral insulin signalling system and AdipoR1 but not AdipoR2 expression. As AdipoR2 but not AdipoR1 expression seems to correlate with invasiveness, we assume different functions of the two adiponectin receptors in breast cancer.     

The management of menopausal symptoms in breast cancer survivors: A case-based approach

Introduction

The intensified treatment of breast cancer improves survival but has a price in terms of side-effects. The main side-effects, such as vasomotor symptoms and impaired sexual functioning, are related to premature menopause due to chemotherapy and/or anti-hormonal therapy. Though for some women these symptoms are bearable, for others they have a large impact on their quality of life. The paper discusses the menopausal symptoms most frequently reported by breast cancer survivors and current treatment options.

Methods

A literature review is presented of menopausal symptoms after breast cancer and management strategies, illustrated by two cases.

Summary

Vasomotor symptoms can be relieved by lifestyle adaptation, acupuncture and non-hormonal agents such as venlafaxine, gabapentin or clonidine. Impaired sexual functioning can be treated by couple-based sexual counselling or psycho-educational therapy. Painful intercourse due to vaginal dryness can be alleviated by vaginal lubricants and moisturizers, but is most effectively treated by vaginal estriol. Local estriol seems safe if used for a short period (less than six weeks). Because of proven increased risk of recurrence with hormone replacement therapy (HRT), it should not be prescribed for breast cancer survivors, although exceptions could be made of selected cases of fully informed BRCA mutation carriers after ER-negative breast cancer and with severe menopausal symptoms due to prophylactic oophorectomy at a young age and (preferably) after mastectomy.

Conclusion

The management of vasomotor symptoms and impaired sexual functioning in breast cancer survivors should focus on lifestyle and, if necessary, non-hormonal pharmacological interventions.     

Postmenopausal hormone drugs and breast and colon cancer: Nordic countries 1995-2005

Objectives

The purpose of this study was to utilize the variation in the level and timing of the change in postmenopausal hormone therapy (HT) use between the Nordic countries to assess the population-level impact of decline in HT use on the breast and colon cancer incidences.

Methods

Nationwide HT-sales data in defined daily doses (DDDs) per 1000 inhabitant in 1995–2005 in Finland, Iceland, Norway and Sweden were obtained from drug control authorities. Breast and colon cancer incidence data by 5-year age-groups were obtained from the National Cancer Registers. By time series analysis we estimated in each age-group and country how much a change in HT-sales changes cancer incidence.

Results

The decline of HT-sales varied; the decline from the highest sales was 61% in Sweden, 51% in Norway, 43% in Iceland and 25% in Finland. With the exception of Finland, the breast cancer incidence increased from 1995 to the year following the year with maximum HT-sales and decreased after that year. In the model combining countries and years, changes in HT-sales predicted the change in breast cancer incidence, an average 7% for each 10 DDD units of HT-sales. No clear association between HT-sales and colon cancer incidence was found.

Conclusions

The time and country specific data suggest, that on the population level, a notable drop from high level of HT use somewhat decreases breast cancer incidence or breaks its increasing trends. The suggested protective effect of HT for colon cancer was not seen.     

Big gap between risk perception for breast cancer and risk factors: Nationwide survey in Korea

Objective

To explore perceived risk of breast cancer among Korean women and to investigate factors associated with perceived risk of breast cancer.

Methods

A telephone survey using random digit dialing was conducted with an age- and region-stratified random sample of women in Korea. The study population consisted of 1000 women who participated in telephone surveys in which a 21-item questionnaire was administered.

Results

This study showed a significant level of comparative optimism in breast cancer risk perception in Korean women with an average risk of breast cancer. According to the multivariate analysis, younger age, family history of breast cancer, and history of benign breast disease were the factors associated with higher perceived comparative risk of breast cancer.

Conclusion

The finding that a limited number of breast cancer risk factors were related to perceived risk of breast cancer is worrying because women with other risk factors for breast cancer may believe themselves to be at lower risk.

Practice implications

It is necessary for women to understand their risk factor profiles to avoid biased optimism or pessimism.     

A cross-sectional study of elderly Asian and European women with primary operable breast cancer aged 70 and older. Are there differences?

Background

Breast cancer (BC) is becoming a disease of the elderly. Additionally, BC-incidence is rising in Asia. The aim of this study was to explore clinico-pathological characteristics and differences of breast cancer in elderly Asian/Han-Chinese compared to Caucasian/Austrian women.

Methods

A total number of 630 consecutive primary operable, unilateral breast cancer cases, 70 years and older, were analyzed. Histo-pathological findings and biological characteristics of 198 Caucasian/Austrian were compared with 432 Asian/Han-Chinese. Pearson's chi-square test was used to assess differences in the analyzed populations.

Results

A significantly higher rate of triple-negative BC (p = 0.027) was diagnosed among the Chinese geriatric population. More estrogen-receptor positive BC was detected in the Caucasian study group (p < 0.001). No statistically significant differences were detected based on tumor size, axillary lymph-node status, nor HER2-receptor expression.

Conclusion

This study will help us gain additional ethnic-specific insight into the biological characteristics of breast cancer in the elderly Caucasian/Austrian and Asian/Han-Chinese populations.     

HSP90在乳腺癌细胞增殖中的作用与机制研究

目的： 应用热休克蛋白90(HSP90)功能特异性抑制剂格尔德霉素(GA)研究HSP90在乳腺癌细胞增殖中的作用，进而探讨相关机制。方法: 培养人乳腺癌细胞株MDA-MB-435s，采用MTT法检测GA对MDA-MB-435s细胞的生长抑制作用，流式细胞术分析细胞周期，应用Western免疫印迹法检测细胞内Stat3磷酸化状态和突变型p53表达变化。结果: 不同浓度GA对乳腺癌MDA-MB-435s细胞有生长抑制作用，呈时效量效依赖关系，GA作用后细胞呈现G2/M期阻滞。400 nmol/L GA作用48h后，细胞内Stat3磷酸化水平明显低于对照组，同时突变型p53表达明显低于对照组。结论: 抑制HSP90功能可明显抑制乳腺癌MDA-MB-435s细胞的增殖，此与下调细胞内Stat3磷酸化水平和突变型p53表达有关。     

Development of a shared decision making coding system for analysis of patient-healthcare provider encounters

Objectives

To describe the development and refinement of a scheme, detail of essential elements and participants in shared decision making (DEEP-SDM), for coding shared decision making (SDM) while reporting on the characteristics of decisions in a sample of patients with metastatic breast cancer.

Methods

The evidence-based patient choice instrument was modified to reflect Makoul and Clayman's integrative model of SDM. Coding was conducted on video recordings of 20 women at the first visit with their medical oncologists after suspicion of disease progression. Noldus Observer XT v.8, a video coding software platform, was used for coding.

Results

The sample contained 80 decisions (range: 1–11), divided into 150 decision making segments. Most decisions were physician-led, although patients and physicians initiated similar numbers of decision-making conversations.

Conclusion

DEEP-SDM facilitates content analysis of encounters between women with metastatic breast cancer and their medical oncologists. Despite the fractured nature of decision making, it is possible to identify decision points and to code each of the essential elements of shared decision making. Further work should include application of DEEP-SDM to non-cancer encounters.

Practice implications

A better understanding of how decisions unfold in the medical encounter can help inform the relationship of SDM to patient-reported outcomes.     

Circulating estradiol defines the tumor phenotype in menopausal breast cancer patients

Objective

To correlate circulating hormone levels with the clinical and biological features of the tumors in menopausal breast cancer patients.

Design

Circulating hormone levels were measured in 161 previously untreated menopausal breast cancer patients within 72 h of their planned surgery. The obtained hormone levels were correlated with tumor size, histological and nuclear grade, histological score, axillary nodal status, DNA-ploidy and Ki67-, c-erb-B2-, p53, Bax-, VEGF- and Nup88-expression.

Results

The only statistically significant correlations found between circulating hormone levels and all tested variables were an inverse one between estradiol and the expression of the apoptosis-associated Bax gene (p = 0.009), and again an inverse correlation between estradiol and the expression of c-erb-B2 (p = 0.04). When comparing hormone levels with each other, a significant correlation between estradiol and progesterone (p < 0.0001), an inverse one between estradiol and FSH (p = 0.04) and a direct one between LH and prolactin (p = 0.001) were found.

Conclusion

Higher circulating estradiol levels in postmenopausal breast cancer patients are associated with molecular features usually defining a biologically less aggressive tumor phenotype.     

Perception of cancer recurrence risk: More information is better

Objective

Breast cancer is the most common cancer among women worldwide. Given the advances in extending survival, the number of recently diagnosed breast cancer patients and longer-term breast cancer survivors is growing. The goals of this study were to better understand (1) perceptions of provider cancer recurrence risk communication, (2) perceived risk of breast cancer recurrence in cancer patients and survivors, and (3) accuracy of perceived risk.

Methods

A survey was conducted on women with a prior breast cancer (n = 141).

Results

Approximately 40% of women perceived that providers had not talked about their breast cancer recurrence risk; although only 1 person reported not wanting a physician to talk to her about her risk. Women were largely inaccurate in their assessments of risk. Greater worry, living in a rural area, and longer time since diagnosis were associated with greater inaccuracy. Women tended to think about distal recurrence of cancer as often of local recurrence.

Conclusions

Perceived risk of breast cancer recurrence was inaccurate, and patients desired more communication about recurrence risk.

Practice implications

Consistent with findings from other studies, greater efforts are needed to improve the communication of cancer recurrence risk to patients. Attention should be paid to those from rural areas and to distal cancer recurrence in women with a previous history of breast cancer.     

The efficacy of surgical treatment of cancer – 20 years later

Introduction

Cancer treatment will be effective only if it is be based on a valid paradigm of what cancer is and therefore capable of affecting the course of the disease. A review in 1993 found no evidence that surgery affected the course of the disease and an alternative paradigm was proposed. A review of mammography screening trials in 1996 found no benefits from breast cancer screening. This was predicted by this alternative paradigm. This review updates the evidence twenty years later.

Aim

To identify evidence that the primary treatment of cancer, surgery, has been shown to affect the course of the disease.If there is no such evidence, then to identify the correct paradigm of what cancer is from other cancer treatments that have been shown to be effective.

Method

Because surgery has never been shown in a randomised controlled trial to affect the course of cancer seven other indirect methods were used to evaluate its efficacy.

Results

None of the seven indirect methods used showed that surgery clearly affects the course of the disease for any type of cancer. The lack of benefits from cancer screening now includes not only from breast cancer but also from bowel, lung, prostate and ovarian cancer screening. This confirms that cancer surgery is based on an invalid paradigm of what cancer is. Survival figures following treatments based on an alternative paradigm that assumes cancer is a systemic disease were found to be superior to those following surgery, reinforcing the conclusion that cancer is a systemic disease and that cancer surgery is unlikely to be of benefit in most cases.

Conclusion

No benefits can be expected to be achieved from using cancer surgery except in a few immediately life-threatening situations. Surgery appears to be based on an invalid paradigm of what cancer is. Cancer appears to be a systemic disease and therefore standard treatments need to be reassessed in this light.