The latest medical developments in the world of breast cancer and cancer, from Google Alerts, for the week ending 5 September 2014.
Last week’s Best of Breast (w/e 29 August 2014) covered the controversy over whether cancer is curable or not. Now, I know there are many people who are in long-term remission, but remission is not a cure. The current thinking is that cancer is a chronic disease, it may go into latent mode, but it may re-surface years later.
This week seems to be the week of the metastasis – scientists are discovering more ways in which cancer cells cannily inveigle themselves into other parts of the body. It’s nothing new … there have been similar discoveries every week, every month, every year. The problem seems to be putting this research into practice and finding ways of blocking the proteins or enzymes or rogue signalling-pathways that cause cancer to metastasise.
1. Stopping cancer from forming tentacles stops metastasis
- To spread, or “metastasize,” cancer cells must enter the blood stream or lymph system, travel through its channels, and then exit to another area or organ in the body.
- This final exit is the least understood part of the metastatic process.
- Previous research has shown cancer cells are capable of producing “invadopodia,” a type of extension that cells use to probe and change their environment.
- However, until recently, their significance in the escape of cancer cells from the bloodstream has been unclear.
- In the study, the scientists injected fluorescent cancer cells into the bloodstream of test models, and then captured the fate of these cells using high-resolution time-lapse imaging.
- Results confirmed the cancer cells formed invadopodia to reach out of the bloodstream and into the tissue of the surrounding organs – they essentially formed “tentacles” that enabled the tumor cell to enter the organ.
- However, through genetic modification or drug treatment, the scientists were able to block the factors needed for invadopodia to form. This effectively stopped all attempts for the cancer to spread.
- The study findings confirm invadopodia play a key role in the spread of cancer. Most importantly, they suggest an important new target for therapy. If a drug can be developed to prevent invadopodia from forming, it could potentially stop the spread of cancer.
For more information: Cell Reports, DOI: http://dx.doi.org/10.1016/j.celrep.2014.07.050, Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis
2. ‘Prepped’ by tumor cells, lymphatic cells encourage breast cancer cells to spread
- Breast cancer cells can lay the groundwork for their own spread throughout the body by coaxing cells within lymphatic vessels to send out tumor-welcoming signals, according to a new report by Johns Hopkins scientists.
- The researchers describe animal and cell-culture experiments that show increased levels of so-called signaling molecules released by breast cancer cells.
- These molecules cause lymphatic endothelial cells (LECs) in the lungs and lymph nodes to produce proteins called CCL5 and VEGF.
- CCL5 attracts tumor cells to the lungs and lymph nodes, and VEGF increases the number of blood vessels and makes them more porous, allowing tumor cells to metastasize and infiltrate the lungs.
- In the same report, the researchers say maraviroc, a drug already approved for treating HIV infection, blocked the siren call of CCL5 in tests on animals and cells and prevented tumor spread (metastasis).
- Additional experiments using a combination of maraviroc and a drug that blocks the VEGF protein suggest that the treatment duo could be an effective way to prevent metastatic disease in human breast cancer patients, according to the researchers.
- Popel and colleagues traced the influence of tumor signaling on LECs in cell cultures and in mice.
- Breast cancer cells were bathed in a nutrient-rich liquid, and, as the cancer cells grew, the investigators detected secretions of a signaling molecule called interleukin-6 (IL6) in the liquid.
- Mice that were injected with the IL6-containing liquid experienced a continual rise in CCL5 levels in blood samples for several weeks. Nine of 10 tumor-bearing mice injected with the IL6-laden liquid developed metastases five weeks later. Only two of 10 mice, exposed to the liquid and given a combination of maraviroc and a VEGF-blocking drug, developed metastases.
- Because maraviroc blocks the actions of CCL5, it could be delivered, along with standard chemotherapy, right after surgically removing a tumor in a bid to prevent any leftover circulating tumor cells from finding a new metastatic niche in the body, Popel says.
- “However, IL6-secreting tumors could be laying the groundwork for metastasis much earlier than surgery occurs in a patient,” he said. “To prevent metastatic sites from taking root, we could administer drugs that block IL6 before surgery.”
For more information: Nature Communications 5, Article number: 4715doi:10.1038/ ncomms5715, Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis
3. Enzyme Controlling Metastasis of Breast Cancer Identified
- Researchers at the University of California, San Diego School of Medicine have identified an enzyme that controls the spread of breast cancer.
- The enzyme, called UBC13, was found to be present in breast cancer cells at two to three times the levels of normal healthy cells.
- Although the enzyme’s role in regulating normal cell growth and healthy immune system function is well-documented, the study is among the first to show a link to the spread of breast cancer.
- The enzyme regulates cancer cells’ ability to transmit signals that stimulate cell growth and survival by regulating the activity of a protein called p38 which when “knocked down” prevents metastasis.
- Of clinical note, the researchers said a compound that inhibits the activation of p38 is already being tested for treatment of rheumatoid arthritis.
- In their experiments, scientists took human breast cancer cell lines and used a lentivirus to silence the expression of both the UBC13 and p38 proteins.
- These altered cancer cells were then injected into the mammary tissues of mice.
- Although the primary tumours grew in these mice, their cancers did not spread.
For more information: PNAS, doi: 10.1073/pnas.1414358111, Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade
4. Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
- LKB1, also known as STK11, is a master kinase that serves as an energy metabolic sensor and is involved in cell polarity regulation.
- Recent studies have indicated that LKB1 is related to breast tumorigenesis and breast cancer progression.
- Low expression of LKB1 was significantly associated with established markers of unfavorable breast cancer prognosis, such as loss of ER/PR, E-cadherin and HMW-CK.
For more information: Journal of Experimental & Clinical Cancer Research 2014, 33:70, Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
5. Strong link between high fat diets, intestinal bacteria, and bowel cancer
- The study points to bacteria playing a central role in the development and growth of bowel tumours.
- Working with mice, the researchers showed that fatty food shifted the composition of gut flora – the diverse population of bacteria that inhabit the digestive tract.
- This in turn reduced the level of immune system defences against cancer.
- The effect was seen in non-obese mice with a mutant version of a gene called Kras that is known to be associated with human bowel cancer.
- Treatment to wipe out the bacteria or mimic the presence of protective “friendly” bugs was found to slow down tumour progression.
- “Diet-associated cancer development may be based on marked shifts in bacterial communities rather than on the development of obesity and metabolic disorder.
- “Thus, personalised dietary interventions might allow an individual’s microbiota (flora) to be modulated to promote health, especially in those who are at a high risk because of genetic susceptibility and a high fat intake.”
- Another discovery was that bowel cancer could be “transmitted” via bacteria-laden faecal samples.
- When the samples from mice with bowel tumours were transferred to other healthy animals with the Kras mutation, this was enough to trigger cancer even in the absence of a high fat diet.
- Treating mice with bowel cancer with antibiotics to kill their gut bacteria led to a slowdown in tumour progression.
- The same effect followed treatment with butyrate, a fatty acid produced in the gut by the fermenting action of “friendly” bacteria.
- Butyrate is a widely available supplement said to benefit people with inflammatory bowel conditions such as Crohn’s disease.
For more information: Nature(2014)doi:10.1038/nature13398, High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity
6. Prognostic Value of Circulating Tumor Cells after Chemotherapy in Early Breast Cancer
- The detection of circulating tumor cells (CTCs) has been shown to predict reduced survival outcomes in metastatic breast cancer but not in the earlier stage of disease—until now.
In a new study, CTCs were analyzed in 2,026 patients before adjuvant chemotherapy and in 1,492 patients after chemotherapy for early breast cancer.
CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45.
Before chemotherapy, CTCs were detected in 21.5% of patients, with 19.6% of node-negative, and 22.4% of node-positive patients showing CTCs.
No association was found with tumor size, grading, or hormone receptor status.
After chemotherapy, 22.1% of patients (330 of 1,493) were CTC-positive.
The presence of CTCs was associated with poor disease-free survival (DFS), distant DFS, breast cancer–specific survival, and overall survival.
Additionally, CTCs were confirmed as independent prognostic markers in multivariable analyses.
The prognosis was the worst in patients with 5 or more CTCs per 30 mL blood.
The presence of persisting CTCs after chemotherapy showed a negative influence on Disease-Free Survival (DFS)
These results are described as the first to suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.
For more information: J Natl Cancer Inst. 2014;106(5), PMID: 24832787, Circulating tumor cells predict survival in early average-to-high risk breast cancer patients
7. ASCO Updates Guidelines for HER2-Negative Advanced Breast Cancer
- The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on both targeted therapies and chemotherapy treatment for women with HER2-negative breast cancer, which makes up approximately 80% of all breast cancers diagnosed in the United States.
- According to the guideline, hormonal therapy, rather than chemotherapy, is the preferred first-line therapy for patients with estrogen receptor–positive metastatic breast cancer, except in cases of immediate life-threatening disease or when a patient is suspected to be resistant to hormonal treatment.
- Subsequent therapy should consist of sequential chemotherapy.
- There is no single agent that is preferred as a first-line or later-line therapy.
- Rather, the decision should be based on patient factors, including prior therapies, toxicity, performance status, comorbidities, and the patient’s preference.
- It was also stressed that the role of bevacizumab for breast cancer is still controversial
8. Molecular pump solves issue of how to get enough drug into tumor without harming normal cells
For more information: Nature Medicine20,1062–1068(2014)doi:10.1038/nm.3623, In vivo proteomic imaging analysis of caveolae reveals pumping system to penetrate solid tumors
9. Radiotherapy trial: once-weekly breast radiation following lumpectomy as successful as daily radiation
- Traditionally, American doctors have favored the standard regimen of small daily radiation doses after lumpectomy for cancer control.
- But day-to-day radiation for a period of six to seven weeks can cause great inconvenience to the patients with regard to the associated costs.
- Breast cancer oncologists have recently devised a regimen that involves only once-weekly breast radiation following lumpectomy, instead of the standard practice of daily radiation.
- The interim results of the five-year Phase 2 clinical trial using the experimental regimen shows better completion results at lower costs and the same cosmetic results as daily radiation therapy.
- This new regimen reduces the total treatment time by about one-fourth to one-third of the current daily-treatment.
- Since insurers reimburse on a per-radiation basis, this regimen also lowers costs.
For more information: Dragun A et al. A phase 2 trial of once-weekly hypofractionated breast irradiation: Interim analysis of cosmetic outcome and quality of life. Breast Cancer Symposium 2014
10. Neoadjuvant Regimen Beneficial in Triple-Negative Breast Cancer
- Triple-negative breast cancer (TNBC) is associated with a poorer prognosis than other types of breast cancer.
- A recent study investigated the addition of carboplatin, bevacizumab or their combination to conventional anthracyline- and taxane-based neoadjuvant chemotherapy (NACT) in 443 patients with stage II to III TNBC.
The authors concluded that the addition of either carboplatin or bevacizumab to NACT increased pCR rates in stage II to III TNBC, but that further research is required to characterize the effect of this regimen on relapse-free or overall survival.