| The Breast Cancer Network News for:
Thursday, August 2, 2018
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LA JOLLA, CA - July 25, 2018 - Scientists at Scripps Research have uncovered a new strategy to kill tumors, including some triple-negative breast cancers, without harming healthy cells, a discovery that could lead to more ways to treat tumors while reducing side effects. The study, published recently in Nature Communications, shows that a molecule in cells, called Rad52, repairs special kinds of damaged DNA that accumulate in some cancers. A future therapeutic could inhibit Rad52, robbing cancer cells of this repair mechanism. “This could give us a way to kill tumors without harming normal cells,” says Xiaohua Wu, PhD, professor at Scripps Research and senior author of the study. “That’s the future. That’s the goal for targeted cancer treatments—to make these treatments a part of precision medicine.” Wu and her colleagues investigate how seemingly healthy cells become cancerous, with an eye toward leveraging differences between cancers and healthy cells to develop new therapeutic approaches. The culprits may be different from patient to patient, so the key to killing specific cancer types is to study the basic roles of proteins—and how things go awry in different cancers. “The most important thing is to understand the defects in all these tumors, and then you can understand how to target them specifically,” says Wu. One cancer subtype is triple-negative breast cancer, which make up 10 to 20 percent of breast cancer diagnoses. This aggressive form strikes an estimated 28,000 Americans each year. The new research shows how to exploit a weakness in some triple-negative breast cancers. Some of these tumors have a deficient version of the gene that codes for a protein called FANCM. Normally, this protein protects regions of DNA called common fragile sites, which are prone to breaking when cells divide. Wu’s team found that FANCM-deficient tumors have to call in a backup team to repair DNA. That’s when the protein Rad52 steps in to repair DNA damage in these tumors. This finding came as a surprise because Rad52 plays no essential role in healthy cells. Next, the researchers tested what would happen if they stopped Rad52 from working in FANCM-deficient cells. As they suspected, the cells accumulated double-strand breaks at common fragile sites. With no way to repair these breaks, the cells died. Follow-up experiments in a mouse model showed that suppressing Rad52 in FANCM tumors dramatically reduced cell and tumor growth. This phenomenon, when a cell only dies because of a combination of two defects, is called synthetic lethality. Only cells with both defects will die. This means drugs inhibiting Rad52 would not harm healthy cells, which do have sufficient FANCM. Only FANCM-deficient cells, like those seen in some triple-negative breast cancers, would die. “Normal cells are fine when you remove Rad52, so we think potential therapies would have a very low toxicity,” Wu says. Exploiting synthetic lethality is emerging as a crucial strategy in cancer drug design. In fact, the U.S. Food and Drug Administration recently approved several drugs called PARP inhibitors, which also take advantage of synthetic lethality to kill tumors with BRCA mutations. Wu says the next step in this project is to develop potent small molecule inhibitors of Rad52 that could be tested as a drug candidate for a new targeted cancer therapy. “This study shows why it’s very important to focus on basic research and then follow-up on findings that can benefit patients,” Wu says.
Common fragile sites (CFSs) are prone to chromosomal breakage and are hotspots for chromosomal rearrangements in cancer cells. We uncovered a novel function of Fanconi anemia (FA) protein FANCM in the protection of CFSs that is independent of the FA core complex and the FANCI–FANCD2 complex. FANCM, along with its binding partners FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences, where it suppresses DNA double-strand break (DSB) formation and mitotic recombination in a manner dependent on FANCM translocase activity. Interestingly, we also identified an indispensable function of Rad52 in the repair of DSBs at CFS-derived AT-rich sequences, despite its nonessential function in general homologous recombination (HR) in mammalian cells. Suppression of Rad52 expression in combination with FANCM knockout drastically reduces cell and tumor growth, suggesting a synthetic lethality interaction between these two genes, which offers a potential targeted treatment strategy for FANCM-deficient tumors with Rad52 inhibition. [NOTE: For the full paper, please follow the supplied link.]
Introduction: Cancer treatment-induced bone loss (CTIBL) is a long-term side effect of breast cancer therapy. Both calcitriol and weight-bearing exercise improve bone metabolism for osteoporotic patients, but are unproven in a breast cancer population. We used a novel high-dose calcitriol regimen with an individualized exercise intervention to improve bone metabolism in breast cancer survivors. Methods: We accrued 41 subjects to this open label, 2 × 2 factorial, randomized feasibility trial. Breast cancer survivors were randomized to receive the following: (1) calcitriol (45 micrograms/week), (2) individualized exercise with progressive walking and resistance training, (3) both, or (4) a daily multivitamin (control condition) for 12 weeks. Primary outcomes included changes in biomarkers of bone formation, bone resorption, and the bone remodeling index, a composite measure of bone formation and resorption. Safety measures included clinical and biochemical adverse events. A main effect analysis was used for these endpoints. Results: Hypercalcemia was limited to three grade I cases with no grade ≥ 2 cases. Among exercisers, 100% engaged in the prescribed aerobic training and 44.4% engaged in the prescribed resistance training. Calcitriol significantly improved bone formation (Cohen’s d = 0.64; p < 0.01), resulting in a non-significant increase in the bone remodeling index (Cohen’s d = 0.21; p = 31). Exercise failed to improve any of the bone biomarkers. Conclusions: Both calcitriol and exercise were shown to be feasible and well tolerated. Calcitriol significantly improved bone formation, resulting in a net increase of bone metabolism. Compliance with the exercise intervention was sub-optimal, which may have led to a lack of effect of exercise on bone metabolism.
Background and Objectives: Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC. Methods: This was a retrospective study conducted at the CHU de Québec—Université Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow‐up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy. Results: The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER‐positive (98.2%), PgR‐positive (69.5%), and HER2‐negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13‐year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13‐year OS was 95.8% in NO patients compared to 90.0% for N1‐3 (P = 0.01). Conclusion: Despite the general popular belief that patients with TC fare better than patients with IDC, the 13‐year OS of TC was similar to that of grade I IDC.
Objective: Reproductive decision making for couples with hereditary breast and ovarian cancer (HBOC) is complex and can result in decisional conflict or regret. This study investigated couples' support needs and aimed to identify vulnerable couples. Ultimately, we should strive to develop a clear standard of care guideline regarding reproductive decision support. Methods: Mixed methods were used for data collection. A focus group study was conducted among 18 couples (N = 35) with HBOC who had made a reproductive decision after reproductive counselling. Subsequently, 129 similar couples (N = 258) were invited to complete a cross‐sectional survey based on the focus group study. Results: Clinical and practical aspects of reproductive counselling were positively evaluated in the focus group study, although couples indicated a need for additional support with emotional and social concerns in which their relationship, social environment, and the way they picture their desired family were key elements. The survey was completed by 86 participants. Making a reproductive choice was experienced as (very) difficult by 43%, and 69% showed a need for additional support during decision making. Younger participants and those who opted for a natural pregnancy experienced more difficulty with reproductive decision making, and partners showed a higher need for psychological support than carriers. Conclusions: Couples with HBOC who need to make a reproductive decision have specific needs for guidance and support, of which the desired content and methods can vary. It is therefore important to identify vulnerable couples and to attune counselling to couples' needs.
Purpose: This aim of this study was to determine the use of compression garments by women with lymphoedema secondary to breast cancer treatment and factors which underpin use. Methods: An online survey was distributed to the Survey and Review group of the Breast Cancer Network Australia. The survey included questions related to the participants’ demographics, breast cancer and lymphoedema medical history, prescription and use of compression garments and their beliefs about compression and lymphoedema. Data were analysed using principal component analysis and multivariable logistic regression. Results: Compression garments had been prescribed to 83% of 201 women with lymphoedema within the last 5 years, although 37 women had discontinued their use. Even when accounting for severity of swelling, type of garment(s) and advice given for use varied across participants. Use of compression garments was driven by women’s beliefs that they were vulnerable to progression of their disease and that compression would prevent its worsening. Common reasons given as to why women had discontinued their use included discomfort, and their lymphoedema was stable. Participant characteristics associated with discontinuance of compression garments included their belief that (i) the garments were not effective in managing their condition, (ii) experienced mild-moderate swelling and/or (iii) had experienced swelling for greater than 5 years. Conclusion: The prescription of compression garments for lymphoedema is highly varied and may be due to lack of underpinning evidence to inform treatment.
Objective: Physical activity (PA) and a healthy diet can improve the well‐being of cancer survivors. However, cancer survivors often do not engage in these behaviours. This study aimed to explore barriers and facilitators to engaging in these behaviours following cancer treatment. Methods: During the development of a Web‐based intervention to enhance health‐related quality of life in cancer survivors, 32 people who had completed treatment for breast, colon, or prostate cancer were presented with an intervention for PA and healthy eating. In‐depth think‐aloud and semi‐structured interviewing techniques were used to elicit perceptions of both behaviours. Data were analysed using thematic analysis. Results: Some individuals reported implementing positive health behaviour changes to maintain health and prevent recurrence, or to help them to move forward after cancer. However, others reported feeling abandoned, and many did not report an intention to engage in lifestyle changes. Individuals discussed contextual and health‐related barriers that were specifically linked to their situation as post‐treatment cancer survivors: individuals described uncertainty about how to implement adaptive changes and perceived a lack of support from health care providers. Others viewed behaviour change as unnecessary or undesirable, with some arguing that non‐modifiable factors contributed more to their cancer diagnosis than lifestyle‐related factors. Conclusions: For many participants in this study, the period that follows treatment for cancer did not represent a “teachable moment.” A variety of complex and heterogeneous factors appeared to impact motivation and may limit cancer survivors from engaging with diet and PA changes.
The 2018 International Cancer Education Conference (ICEC) will occur on October 3–5, 2018 in Atlanta, Georgia, co-organized by the American Association for Cancer Education (AACE), the Cancer Patient Education Network (CPEN), and the European Association for Cancer Education (EACE). This year’s theme is Cancer Education: Bridging the Gap Through Health Equity, Innovation, and Advocacy in Global Communities. Having this conference in Atlanta is of particular significance, given the rich histories of this city and the participating organizations. I believe that Dr. Martin Luther King Jr., 50 years now departed, is smiling down in anticipation of this event.
A new study reveals that several drugs for treating haematological cancers are less effective than expected in inhibiting a special enzyme. Researchers have also identified new lead compounds that could potentially improve existing treatments and pave the way for new drugs against diabetes and obesity. Almost all medical treatments are based on drugs that inhibit the activity of proteins in the body leaving them unable to contribute to the development of for example tumours, inflammatory diseases or metabolic disorders such as diabetes and obesity. A number of drugs that target a group of proteins – the so-called HDAC enzymes – have attracted significant attention in recent years from researchers and drug developers, because they contribute to the development of resistance towards cancer treatments. New research has demonstrated that they also play a crucial role in a whole range of other diseases that are due to dysregulation of human genes. An organic chemistry research team at the Faculty of Health and Medical Sciences, University of Copenhagen, has been investigating all the 11 HDAC enzymes expressed in human cells to develop specific molecules that can bind to the enzymes and block their activity in the body. In a study just published by the esteemed scientific journal Cell Chemical Biology, the researchers carried out a wide range of tests using chemically designed molecules to reveal the activities of HDAC enzymes and provide insights into their function at the molecular level. To their great surprise, they made a number of new, undescribed discoveries related to the HDAC11 enzyme. ”We have found a handle that will enable the identification of new inhibitors and this could potentially play a vital role in the development of drugs to treat several diseases," says Prof. Christian Adam Olsen, Center for Biopharmaceuticals at the University of Copenhagen. Fact Box: The study shows that HDAC11 can cleave unexpected modifications on the surface of proteins. Proteins consist of long chains of 20 different amino acids in different sequences produced by the ribosome. The surfaces of proteins are also subsequently chemically modified in cells. It turns out now that HDAC11 affects specific variants of these modifications. By constructing chemical molecules that can bind to and regulate HDAC11, researchers can inhibit disease-causing mechanisms and the body's production of damaged cells. Poor efficacy of approved drugs As part of the study, the researchers investigated a range of existing drugs for treating haematological cancers, including leukaemia and lymphoma, and other well known HDAC inhibitors. Surprisingly, it turned out that several of the existing inhibitors were unable to block the newly-discovered enzymatic activity of HDAC11. ”This was the second major surprise in the study and suggests that the efficacy of HDAC-targeting drugs against the HDAC11 enzyme should be reassessed. For a long time, many HDAC inhibitors were believed to affect HDAC11 but we now have to question that. On the other hand, we have identified potent inhibitors from our compound library that we can use as the starting point for identifying new candidates with the potential for developing drugs,” says Christian Adam Olsen. Extensive drug target library The study was based on extensive tests with the 11 human HDAC enzymes. Simultaneously with international research groups, the researchers developed chemically modified substrates for in vitro screening of enzymatic activity. This has now resulted in an extensive library providing an overview of the enzymatic activities of HDACs against a variety of protein modifications in vitro. The researchers applied their discovery to develop the first efficient assay for determining the efficacy of drugs against HDAC11 in vitro, which may become important for the future development of drugs against a range of diseases such as diabetes, cancer, inflammatory disease, and autoimmune disease. The study is published in Cell Chemical Biology by Professor Christian Adam Olsen, PhD. student Carlos Moreno-Yruela, Postdoctoral Fellow Iacopo Galleano, and Assistant Professor Andreas Stahl Madsen of the Center for Biopharmaceuticals at University of Copenhagen.
Histone deacetylase (HDAC) enzymes regulate diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function. Here, we show that HDAC11 cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11.
PHILADELPHIA — A diet that encourages both healthy eating and physical activity and discourages alcohol consumption was associated with a reduced overall cancer risk, as well as lower breast, prostate, and colorectal cancer risks, according to an analysis published in Cancer Research, a journal of the American Association for Cancer Research. The study evaluated three previously validated nutritional recommendations: The WCRF/AICR score; the Alternate Healthy Eating Index; and the French Nutrition and Health Program-Guidelines Score, plus one relatively new index, the MEDI-LITE score, which measures adherence to a Mediterranean diet. Researchers found that all the diets were associated with some reduced risk, but the WCRF/AICR recommendations, developed specifically with cancer prevention in mind, had the strongest association with reduced risk. “Among all risk factors for cancer (besides tobacco), nutrition and physical activity are modifiable lifestyle factors which can contribute to cancer risk,” said the study’s senior author, Mathilde Touvier, MSc, MPH, PhD, head of the Nutritional Epidemiology Research Team (EREN) of the French National Institute of Health and Medical Research (Inserm), University of Paris 13. “The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) estimated that in developed countries, around 35 percent of breast cancers and 45 percent of colorectal cancers could be avoided by better adherence to nutritional recommendations. It is, therefore, very important to investigate the role of nutrition in cancer prevention,” added Bernard Srour, PharmD, MPH, and PhD candidate in nutritional epidemiology at EREN-Inserm. In order to examine links between the four nutritional indices and cancer risk, Srour, Touvier, and colleagues drew data from the NutriNet-Santé study, launched in 2009 to investigate associations between nutrition and health in a French cohort. This study included a large sample of 41,543 participants aged 40 or older, who had never been diagnosed with cancer prior to inclusion in the study. The participants completed web-based dietary records every six months, in which they detailed all foods and beverages consumed during a 24-hour period. The researchers then calculated their adherence to each of the four nutritional scores in the study. Between May 2009 and Jan. 1, 2017, 1,489 cancer cases were diagnosed in the study participants, including 488 breast cancers, 222 prostate cancers, and 118 colorectal cancers. The researchers used multivariable Cox proportional hazard models to characterize the associations between each nutritional score and cancer risk. The study showed that a one-point increase in the WCRF/AICR score was associated with a 12 percent decrease in overall cancer risk; a 14 percent decrease in breast cancer risk, and a 12 percent decrease in prostate cancer risk. Adherence to the other diets was also associated with reduced cancer risk, but the WCRF/AICR index demonstrated greater statistical strength and a better predictive performance, Srour and Touvier said. For that reason, and because the other three diets were not specifically designed for cancer prevention, the researchers conducted further analysis on the WCRF/AICR scores, excluding certain components to evaluate the relative importance of each one. They concluded that the “synergistic contribution” of a healthy diet was more significant than any single dietary recommendation. For example, antioxidants from fruits and vegetables may contribute to counteract some of the oxidative damage to the DNA caused by red meat and processed meat, and exercise could lower blood pressure, partly counteracting the effects of high-sodium foods. “This emphasizes the role of an overall healthy lifestyle—nutrition and physical activity and alcohol avoidance—in cancer prevention,” Srour said. “It is, therefore, important to keep in mind that every lifestyle factor counts and it is never too late to adopt a healthy lifestyle.” Srour and Touvier said the WCRF/AICR recommendation to avoid alcohol most likely contributed to that diet’s role in reducing cancer risk. They said the findings in this study augment recent research that implicates alcohol as a risk factor in many cancers. “In its last report, the WCRF stated that there is now strong, convincing evidence that alcohol consumption increases the risks of oropharyngeal, esophagus, liver, colorectal, and post-menopausal breast cancers,” Touvier said, adding that there are also apparent links to stomach and premenopausal breast cancers. The authors said the study’s main limitation is that, as a volunteer-based study, it may have overrepresented women, people with health-conscious behaviors, and those with higher socioeconomic and educational levels. As a result, some unhealthy behaviors may have been underrepresented, and the associations between healthy diets and cancer prevention may be stronger than indicated. Because previous research has shown that the French consume more fruits and vegetables and fewer sugary beverages and processed foods than the American population, the authors said adhering to the WCRF/AICR recommendations would likely yield more dramatic results in an American population. This study was funded by public and governmental grants from agencies including the French Ministry of Health, the French Agency for Public Health (Santé Publique France), the Ile-de-France region, the French National Institute of Health and Medical Research (Inserm) the French National Institute for Agricultural Research INRA, the Conservatoire National des Arts et Métiers, University of Paris 13, Cancéropôle Ile de France, and the French National Cancer Institute. The authors declare no conflict of interest.
Several national and international authorities have proposed nutritional and lifestyle recommendations with the aim of improving health of the general population. Scores of adherence to these recommendations can be calculated at the individual level. Here, we investigated the associations between four nutritional scores and overall, breast, prostate, and colorectal cancer risk in a large prospective population-based cohort: the cancer-specific World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) score, the Alternate Healthy Eating Index 2010 (AHEI-2010), a score based on adherence to the Mediterranean diet (MEDI-LITE), and the French National Nutrition Health Program-Guideline Score (PNNS-GS). This study included 41,543 participants aged ≥40 years from the NutriNet-Santé cohort (2009–2017). A total of 1,489 overall incident cancers were diagnosed. A one-point increment of the WCRF/AICR score was significantly associated with decreased overall [12%; 95% confidence interval (CI), 8%–16%; P < 0.0001], breast (14%; 95% CI, 6%–21%; P = 0.001), and prostate (12%; 95% CI, 0%–22%; P = 0.05) cancer risks. Hazard ratio for colorectal cancer risk was 0.86 (95% CI, 0.72–1.03; P = 0.09). The PNNS-GS score was associated with reduced colorectal cancer risk (P = 0.04) and AHEI-2010 was associated with reduced overall cancer risk (P = 0.03). The WCRF/AICR score performed best. Compared with other tested scores, it included a stronger penalty for alcohol, which is a major risk factor for several cancer sites. Better adherence to nutritional recommendations, especially those designed for cancer prevention, could substantially contribute to decreased cancer incidence. Significance: This large prospective population-based cohort study suggests that following dietary recommendations such as the ones proposed by the World Cancer Research Fund/American Institute for Cancer Research could significantly contribute to cancer prevention.
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