Highlights of medical developments in the world of cancer and breast cancer, from Google Alerts, for the week ending 28 November 2014.
Two topics caught my eye for this week’s round-up: a cancer detection test and research done into tamoxifen resistance.
The cancer test was presented at a Ted talk and what it promises is a “cheap, open-source device that can test blood for several types of cancer at once”. I like the word “cheap”. It means cancer patients can afford to get more frequent testing without worrying about costs. There are loads of different tests out there, some which depend on tumour markers, some on circulating tumour cells, some on growth factors, or inflammation markers in the body. But they all cost money. And the time to be vigilant is not only when you have active disease, but when you are in remission because cancer never goes away … it just becomes latent and you want to detect those treatment-resistant stem cells early on when they rear their ugly heads again.
Tamoxifen, as you probably are aware, is an estrogen antagonist (or blocker), and therefore used for estrogen-positive breast cancer. Tamoxifen-resistance is an interest of mine ever since I discovered that I’m an intermediate metaboliser of tamoxifen and therefore it’s no bloody good taking it in lower doses. In case you are interested, the test for whether or not you are metabolising tamoxifen properly is the cytochrome P450 for the CYP2D6 Genotype test [with thanks to Grace Gawler, cancer strategist, who pointed me in the direction of this test!]. Both the Mayo Clinic and Roche offer this test. Tamoxifen-resistance is something that most cancer patients aren’t aware of. Tamoxifen is touted as a cure-all, but it’s a fact that after some time, cancer cells evolve to find ways around estrogen blockers – clever buggers, and then it’s back to the drawing board to find yet another chemical cosh.
1. New Device Detects Multiple Types Of Cancer With A Single Blood Test
- A startup called Miroculus thinks it has the simple early detection platform that could offer an alternative: a cheap, open-source device that can test blood for several types of cancer at once.
- The platform, dubbed Miriam, finds cancer by extracting RNA from blood, and spreading it across plates that look for specific types of microRNA (molecules that can indicate disease).
- Once it’s hooked up to a smartphone, Miriam sends the information to an online database and compares the microRNA found in the patient’s blood to known patterns that indicate different types of cancer. The process takes an hour.
- Miriam can currently detect lung, breast, and pancreatic cancer at the earliest stages. Eventually, it will be able to detect many more.
- A working prototype of the open source device debuted publicly at the TEDGlobal conference in 2014.
For more information: Jorge Soto’s TEDGlobal talk – the Future of Cancer Detection?
2. Breakthrough in understanding how the immune system recognises cancer
- US researchers have discovered the identity of molecules on the surface of cancer cells which allow the body’s immune system to identify and destroy them.
- The researchers, led by a team at the Memorial Sloan Kettering Cancer Centre in New York, analysed cancer DNA from 64 melanoma patients who had been treated with an immunotherapy drug called ipilimumab (Yervoy), half of whom had responded to the drug.
- Ipilimumab works by switching on the body’s immune system to attack their cancer, but – for unknown reasons – it only works effectively in a minority of patients.
- Having analysed the patients’ cancer DNA, the researchers used sophisticated software to look for genetic mutations in the cancer cells that could predict whether patients had, or hadn’t, responded to the drug.
- In doing so, they uncovered a series of genetic mutations in some of the patients that caused the cancer cells to produce short stretches of protein molecules, called peptide antigens, that make cancerous cells visible to immune response.
- It appears that these mutations cause the antigens to mimic small parts of proteins produced by bacteria and viruses, explaining why they are so effective at triggering the immune response – although the researchers say more research will be needed to confirm this.
- “This is the first time we’ve had an idea of what the immune system actually ‘sees’ on a tumour. Until now, it’s been hot topic of debate.”
For more information: The New England Journal of Medicine, 2014; 371: 2189-2199 December 4, 2014 DOI: 10.1056/NEJMoa1406498, Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
3. New insights into breast cancer spread could yield better tests and treatments
- A study provides the most compelling evidence so far that three types of cells are required for the spread of breast cancer.
- In earlier studies involving animal models and human cancer cell lines, researchers found that breast cancer spreads when three specific cells are in direct contact: an endothelial cell (a type of cell that lines the blood vessels), a perivascular macrophage (a type of immune cell found near blood vessels), and a tumor cell that produces high levels of Mena, a protein that enhances a cancer cell’s ability to spread.
- Where these three cells come in contact is where tumor cells can enter blood vessels—a site called a tumor microenvironment of metastasis, or TMEM.
- Tumors with high numbers of TMEM sites (i.e., they have a high TMEM “score”) were more likely to metastasize than were tumors with lower TMEM scores.
- In addition, the researchers found that cancer tissues high in a form of Mena called MenaINV were especially likely to metastasize. (MenaINV refers to the invasive form of Mena.)
- Breast cancer cells able to cross the endothelial layer in this assay were found to have higher MenaINV levels compared with the total population of patients’ aspirated cells.
- In addition, finding high levels of MenaINV correlated with finding high numbers of TMEM sites in paraffin biopsy specimens from the same patients.
- The Einstein team is currently working with MetaStat, Inc., a biotechnology company located in Montclair, N.J., to develop a commercial TMEM test for assessing a patient’s risk for metastatic breast cancer.
For more information: Sci. Signal., 25 November 2014, Vol. 7, Issue 353, p. ra112, DOI: 10.1126/scisignal.2005329, Invasive breast carcinoma cells from patients exhibit MenaINV– and macrophage-dependent transendothelial migration
4. New Test Predicts Which Early Breast Cancer Will Metastasize
- Current tests that are used for determining prognosis in breast cancer are based on gene signatures found within the tumors ― but a new test under development is focusing instead on the tumor microenvironment.
- The new test, MetaSite Breast test, could be commercially late next year. It relies on determining the tumor microenvironment of metastasis (TMEM) score.
- The story of how TMEM fits into the mechanism of tumor metastasis is not a simple one. In their editorial, Dr Jain and colleagues discuss the “seed and soil” theory of metastasis originally proposed by Paget more than 100 years ago, in which the “seed” is a tumor cell, and its ability to thrive depends on the “soil” of the tumor microenvironment (TMEM).
- According to the editorial, when the tumor travels to its metastatic site (congenial soil), it carries along with it some of the the original “soil” in which it grew.
- Although TMEM is focussed on a trio of cells — tumor cells, macrophages, and endothelial cells lining blood vessels — that are present at the extravasation site, the analysis indicates that preclinical models of metastasis provide evidence that heterotypic clumps of cells that travel to other sites may additionally contain other cells from the original soil in which it grew — fibroblasts, myeloid cells, and stromal cells.
- These observations from animal models suggest that tumor metastasis does not conform to the standard view that “single cancer cells crawl into the blood vessels, adhere downstream to the endothelium, and then transmigrate in a manner similar to leukocytes.”
- The contribution of the tumor microenvironment must therefore be considered in the metastatic process; it is conceivable that it could play a role in the shedding of tumor fragments in circulation and growth and invasion at the secondary site.
- “TMEM is a microanatomical structure that is indicative of tumor cell extravasation and is identifiable and quantifiable in formalin-fixed paraffin-embedded tissue.”
- The microanatomic structure referred to is a trio composed of a tumor cell, a macrophage (a nonspecific immune cell), and an endothelial cell, which lines blood vessels.
- These microanatomic structures are seemingly found in the tumor microenvironment at specific points of entry into the blood stream ― called extravasation sites.
- In the study, TMEM was identified with an immunohistochemical staining procedure using a triple immunostain.
- Three antibodies were applied sequentially to a tumor tissue sample and were developed separately with different “chromogens,” or colored tags.
- The three antibodies separately recognized endothelial cells, macrophages, and Mena, a protein expressed by tumor cells.
- Risk for metastasis increased with an increased TMEM score.
- TMEM score was not associated with metastatic risk in triple-negative breast cancer and HER2+ disease.
- TMEM score was significantly associated with metastatic risk in ER+/HER2- breast cancer — a subgroup of approximately 60% of all patients included in the study.
- TMEM score was more predictive of distant metastasis compared with the IHC4 score (a score that provides prognostic information similar to the Oncotype DX recurrence score).
- TMEM score may be able to define three risk categories for breast cancer metastasis.
- Historically, between 80% and 85% of women with stage I-III breast cancer undergo postoperative chemotherapy. However, only 35% of these cases are biologically capable of metastasizing. “Because we lack good diagnostics, we are overtreating women with chemotherapy, which they may not require.
5. Mutation may explain why anti-hormone therapy does not work for some patients
- A group of investigators has identified a new gene mutation that may explain why some breast cancer patients do not respond to anti-hormone therapy.
- Many breast cancer patients have tumors that are fueled by hormones such as estrogen, which binds to estrogen receptors (ER) in tumor cells.
- The receptors activate ER-dependent genes that, in turn, help ER-positive (ER+) cancers grow.
- ER+ tumors often respond to anti-estrogen agents like tamoxifen, fulvestrant or aromatase inhibitors such as letrozole, anastrazole or exemestane.
- These drugs, referred to as endocrine therapy, are widely used by patients with early and advanced breast cancer.
- However, a significant fraction of patients with ER+ metastatic breast cancer don’t respond to endocrine therapy because their tumors are initially resistant or acquire drug resistance after an initial response to anti-estrogens.
- To identify genetic alterations that help explain this resistance, the investigators profiled ER+ breast tumors from four patients who were treated with the aromatase inhibitor letrozole prior to their mastectomies.
- These tumors did not respond to the letrozole as measured by markers of proliferation in the mastectomy specimens.
- The investigators performed deep sequencing on the tumors and identified a novel mutation (D189Y) in a gene of the Src family of kinases called LYN.
- The authors tested assays in three cell lines and in a mouse model to identify potential therapies for ER+ breast cancers harboring D189Y LYN.
- They tested two Src inhibitors and identified the drug dasatinib as the most effective. Since dasatinib is already approved for another form of cancer, it could be adapted for testing in breast cancer.
- The authors note that the agent is not an ideal drug because it is not a pure LYN inhibitor.
- However, they hope that their identification of the new LYN mutation will spur development of a LYN inhibitor for testing in patients with breast cancer.
For more information: J Clin Invest. 2014;124(11):4737–4752. doi:10.1172/ JCI76375, Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution
6. Exciting Gains in Fighting Breast Cancer Hormone-therapy Resistance
- In the last year, teams from several institutions made an intriguing discovery about relapses in hormone-positive breast cancer.
- Many such relapses may be associated with mutations in ESR1 arising after estrogen deprivation—prompted by prolonged aromatase inhibitor exposure.
- It is too soon for ESR1 mutation-tailored approaches to hit clinical trial.
- But new approaches using old drugs are being considered, and at least one trial of a new drug may be relevant.
- That trial is giving a new oral selective estrogen receptor down-regulator (SERD), ARN810, to patients at MSKCC, Massachusetts General Hospital and Vanderbilt Ingram Cancer Center.
- The work fingers estrogen-deprivation resistance as the culprit, as aromatase inhibitors prevent estrogen production.
- But what about other drugs for hormone-positive cancers, like tamoxifen (a SERM, or selective estrogen receptor modulator) and fulvestrant (the only FDA-approved SERD)?
- “Because tamoxifen and fulvestrant are direct antagonists, they do still inhibit some of these mutated receptors.
- Oncologists are considering boosting doses of these two drugs to see if that might help patients with the ESR1 mutation.
- Preclinical data suggest that the ESR1 mutations confer resistance to estrogen depletion, since they induce ligand (estrogen)–independent ER signaling.”
- They also “still bind to drugs that work directly by binding to the ER, SERMS like tamoxifen, and fulvestrant.
- The new data “suggest ESR1-mutant cells retain some sensitivity to endocrine therapy, higher doses might be required.”
For more information: (1) Chandarlapaty’s 2013 Nature Genetics study (2) Arul Chinnaiyan‘s 2013 Nature Genetics study (3) Cell Reports in September 2013, (4) Cancer Research in December 2013 (5) Clinical Cancer Research in January 2014 (6) Breast Cancer Research and Treatment, February 2014, Volume 144, Issue 1, pp 11-19, Estrogen receptor (ER) α mutations in breast cancer: hidden in plain sight
7. MACROD2 gene may explain why some breast cancers are resistant to tamoxifen
- Researchers have identified a gene, MACROD2, whose presence may explain why some breast cancers are resistant to tamoxifen.
- Tamoxifen generally blocks the binding process of the estrogen-receptor, but some estrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects.
- MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression
- Specifically, the team’s experiments found that when the gene is overexpressed in breast cancer cells—producing more of its protein product than normal—the cells become resistant to tamoxifen.
- Patients who had MACROD2 overexpressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases.
- The team’s analysis also found that MACROD2 overexpression was present in the majority of metastases in patients with tamoxifen-resistant tumors and in tumor cells that had spread from their original site in the breast.
- The latter finding suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug.
For more information: Johns Hopkins Kimmel Cancer Center, http://www.hopkinsmedicine.org
8. Researchers stop ‘vicious cycle of inflammation’ that leads to tumor growth
- A team of scientists have found that inhibiting the activity of an enzyme called autotaxin decreases early tumour growth in the breast by up to 70 per cent.
- It also cuts the spread of the tumour to other parts of the body (metastasis) by a similar margin.
- Autotaxin is responsible for producing lysophosphatidic acid, a signaling molecule that promotes cancer cell survival, growth and metastasis.
- It is also linked to resistance to the beneficial effects of chemotherapy and radiotherapy.
- Autotaxin is normally involved in wound repair and tissue regeneration. It also drives inflammatory conditions such as colitis, arthritis and cancer. It is this inflammation-associated event that is especially problematic and could fuel breast and thyroid tumour growth.
- A tumour is like a wound that does not heal.
- The body hijacks autotaxin to help a tumour grow, resist being killed by chemotherapy and radiotherapy, and to spread to other areas of the body.
- As the tumour grows or is damaged by treatment, it produces more inflammatory mediators, which in turn produce more autotaxin.
- That then increases the production of more inflammatory mediators. The research team found that it could block the growth of breast and thyroid tumours by breaking the vicious cycle with the autotaxin inhibitor, developed by Ono Pharmaceuticals in Japan.
- Daily doses of the drug reduced the initial phase of breast tumour growth by 60 to 70 per cent in experimental models.
- The inhibitor compound also cut tumour metastasis to the lungs by a similar margin.
- Later tests with a different technique for blocking the effects of lysophosphatidic acid enabled the team to block breast and thyroid tumour growth and spread by up to 80 per cent.
- Brindley said his team was surprised when Benesch discovered that autotaxin is not produced by breast cancer cells themselves, but largely by the surrounding breast fat tissue.
- As the tumour develops and causes inflammation in the breast, the fat tissue produces more autotaxin, aggravating the problem by making the tumour grow more, metastasize and resist further treatment.
- By blocking autotaxin the researchers saw a five-fold reduction in inflammation markers in the blood, and a ten-fold reduction in the breast fat tissue adjacent to the tumour.
- The research team is now trying to promote the testing of the compound in human clinical trials in Edmonton—the first autotaxin inhibitor to make it to the clinic after more than 10 years of research.
For more information: FEBS Letters, August 19, 2014 Volume 588, Issue 16, Pages 2712–2727, Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions
9. Could 5:2 diet help to ward off cancer? Scientists say having longer periods without food could be good for us
- Researchers claim we are not designed for three meals a day – and having longer periods of little or no food could be good for us.
- They say intermittent diets, such as the 5:2 system of drastically cutting calories two days a week, could help ward off diseases including breast cancer.
- An international research team reviewing the findings said constantly eating was ‘abnormal’ in evolutionary terms.
- They claim early humans would have eaten sporadically and the habit of three meals a day was only established after the agricultural revolution.
- It is thought severely reducing calories for a short period triggers changes that do not occur if calories are cut just a little each day.
- Dr Harvie, of the charity Genesis Breast Cancer Prevention, showed that dieting for two days a week cuts insulin and leptin – hormones that can fuel breast cancer.
- It may also help burn off dangerous fat that clogs up the liver and fuels heart disease, stroke, diabetes and perhaps even dementia.
- Periods of deprivation give the cells time to repair themselves against the damage that can preceded illnesses from heart disease to cancer.
- ‘When your body is in a fed state, the cells are in growth mode and not in repair mode. It is only in fasting state that your body goes into repair mode and is protected against disease.
- The diet used in the study, the 2-Day Diet, is the forerunner to the highly-popular 5:2 diet.
- It involves two days of eating just 600 to 1,000 calories of low-carbohydrate foods.
- This compares to the 2,000 a woman usually needs and the 2,500 for a man. On the other five days, the dieter eats a healthy Mediterranean diet.
For more information: https://genesisuk.org/2_day_diet/
10. With gene mutations, second breast cancer risk rises over time
- Women who are genetically susceptible to breast cancer and develop it in one breast are at higher than average risk for a tumor in the other breast, and that risk may increase as time goes on, according to a new analysis.
- Mutations in the BRCA 1 or 2 genes increase the risk for several types of cancer and account for 5 percent to 10 percent of breast cancers, according to the National Cancer Institute.
- Researchers from Spain reviewed 20 studies of the risk of cancer in the second breast of BRCA 1 and 2 carriers.
- For breast cancer patients with the BRCA 1 mutation, the risk of a cancer in the opposite breast rose from 15 percent at five years after diagnosis to 27 percent at 10 years and 33 percent at 15 years.
- For the BRCA 2 mutation, the risk increased from nine percent at five years to 19 percent at 10 years to 23 percent at 15 years.
- For women with neither mutation, the risk of cancer in the opposite breast stayed low at 3 percent and 5 percent at the five and 10 year marks, according to results in the journal The Breast. There wasn’t enough data to estimate the 15-year risk in this group.
- Even though the risk for cancer of the second breast is much higher for BRCA carriers, it still means there is a 70 to 80 percent chance that they won’t develop breast cancer 10 to 15 years later.
- In another study in February of this year, women with stage I or II breast cancer and BRCA mutations did survive longer with double vs single mastectomy.
- For women who do not have the BRCA mutations, “patients do often overestimate their contralateral breast cancer risk and do not realize how low it really is.