Best of Breast: news for week ending 28 February 2014

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A summary of Google Alerts for Breast Cancer and Cancer for the week ending 28 February 2014.


Damned if you do … damned if you don’t. image credit:

Monday 3 March was Triple-Negative Breast Cancer Day.  While significant progress has been made in breast cancer research, there is little known about triple negative cancers, even though they impact up to 1 in 5 women diagnosed with breast cancer. TNBC does not have any of the known treatment receptors — meaning that many of the advances in breast cancer treatment don’t work for women diagnosed with TNBC.  For more information: and 

This week’s lead article wades straight into the debate about soy isoflavones as it shows that they cause estrogen-positive breast cancer cells to become more aggressive.  [Bear in mind that the experiments were done on rats and not on humans and some of the signalling pathways in mice/rats are different.]

It has been posited that increased intake of phytoestrogens (which are contained in soy) may be associated with a lower risk of cancer in the breast, although there is controversy surrounding this activity.  Do soy isoflavones increase breast cancer risk?  Should women with breast cancer avoid soy isoflavones: genistein, dadzein, glycitein?

It’s not clear if soy isoflavones affect breast cancer, especially hormone-receptor-positive breast cancers. Isoflavones may affect hormonal therapy’s ability to do its job if both of these molecules compete to get into the same estrogen receptors. If isoflavones deliver a weaker estrogen signal to the receptor compared to tamoxifen (and your body’s estrogen), then the isoflavones might be able to decrease breast cell growth that’s estrogen-dependent. But if the isoflavones give breast cells a stronger estrogen signal than tamoxifen, that’s a problem. [taken from]

I’ve just gone into Pubmed and typed in “soy isoflavones breast cancer” and the search has thrown up 510 articles both for and against soy isoflavones.  It will take me awhile to plough through them.

If you have any comments on this controversy, please post them below.

1.  Soy supplements with isoflavones ‘reprogram’ breast cancer cells to become more aggressive

  • Women with estrogen-responsive breast cancer who consume soy protein supplements containing isoflavones to alleviate the side effects of menopause may be accelerating progression of their cancer, changing it from a treatable subtype to a more aggressive, less treatable form of the disease, new research suggests.
  • The study, published in the journal Molecular Nutrition and Food Research, raises troubling questions about the safety and the potential health consequences associated with long-term use of dietary supplements containing soy isoflavones, such as the phytoestrogen genistein.
  • Scientists at the University of Illinois, Virginia Polytechnic and State University and the National Center for Toxicological Research collaborated on the research.
  • Estradiol and all three genistein concentrations stimulated tumor growth in mice, but when the estradiol implants and higher-dose dietary genistein (750 ppm) were removed, the tumors regressed completely.
  • Tumors also regressed in the mice that consumed the lower dose (500 ppm) of genistein, but the regression terminated with the tumors at significantly larger sizes than those in the control group.
  • In the group that consumed soy protein isolate, tumor regression did not occur during the withdrawal phase – instead, the breast cancer cells continued to grow.
  • “The lower dose of genistein actually does something that is potentially problematic,” said co-author William Helferich, who is a professor in the same department. “A very low dose of genistein effectively reprograms the tumor cells from estrogen-dependent to estrogen independent, converting them into a tumor that no longer needs estrogen to grow and will not respond to many of the current anti-estrogen therapies.”
  • After analyzing gene expression markers, the authors speculate that long-term consumption of the lower dose of genistein elicited changes in the breast cancer cells that reprogrammed them from luminal subtype A – the most common and treatable type of breast cancer – to luminal subtype B, a more aggressive and rapidly growing type of tumor that has a poorer prognosis.
  • “Lifelong consumption of mostly whole-soybean foods such as tofu, tempeh, etc. as is consumed in Asia is probably healthy and protective because Asian populations consume soy as a complex mixture of bioactive compounds and do so throughout their lifetimes,” Helferich said. “However, the way that we consume soy in the West – through highly enriched isoflavones-containing extracts or as dietary supplements, usually later in life – is probably not going to produce the same effects.”
  • The findings of the current study are particularly troubling because they suggest that dietary quantities of soy foods – rather than the highly enriched isoflavone-containing extracts and pure compounds often found in dietary estrogenic supplements for women – may have serious consequences for certain populations, especially breast cancer patients, Helferich said.

For more information:  Molecular Food Nutrition and Research – 24 FEB 2014 DOI: 10.1002/ mnfr.201300780 – Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model

2.  Cancer diagnosis as simple as a pregnancy test

  • Unlike communicable infections like HIV and tuberculosis, signals from tumour proteins are difficult to detect.
  • To get around that problem, the researchers created nano-scale biomarkers that can be injected into the bloodstream.
  • Each marker is designed to interact with specific proteins that are produced by cancer cells. When the two meet, the proteins snip off tiny fragments of the marker. Those fragments eventually find their way into the urine.
  • The test works like a pregnancy test – a person urinates on a paper strip coated with antibodies that can detect the marker fragments. If the fragments are present, the paper displays a line indicating the presence of cancer tissue in the body. Altogether, the process takes about an hour.
  • The research, published this week in PNAS, show that the strip was able to detect colon cancer, as well as blood clots – which can be a sign of cardiovascular problems – in a group of mice. Warren says they can develop more biomarkers to target other types of cancer. The team plans to launch a spin-out company to commercialise the test for use in humans.

For more information:  Journal reference: PNAS, DOI: 10.1073/pnas.1314651111 – Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics

3.  Breast cancer cells less likely to spread when one gene is turned off

  • New research suggests that a protein called Myoferlin, has a significant effect on the risk that breast cancer will spread, and that lowering the protein’s level in cell cultures and mice reduces chances for the disease to extend beyond the initial tumor.
  •  The team of medical and engineering researchers at The Ohio State University previously determined that modifying a single gene to reduce Myoferlin’s level in breast cancer cells lowered the cells’ ability to migrate away from the tumor site.
  • The study showed that mice implanted with breast cancer cells lacking the protein developed small, self-contained tumors consisting of cells that didn’t leave the tumor.
  • In contrast, mice implanted with cancer cells containing the protein developed larger, irregular masses and showed signs that cancer cells had invaded the surrounding tissue.
  • The research suggests that reducing production of the protein, called myoferlin, affects cancer cells in two primary ways: by changing the activation of many genes involved in metastasis in favor of normal cell behavior, and by altering mechanical properties of cancer cells – including their shape and ability to invade – so they are more likely to remain nested together rather than breaking away to travel to other tissues.
  • Myoferlin’s influence on both molecular and mechanical processes in breast cancer cells suggests that diagnostic methods and perhaps even treatments eventually might be tailored to patients based on protein levels and mechanical properties in cells detected in tumors, researchers say.

For more information:  PLOS One – DOI: 10.1371/journal.pone.0086110 – Loss of Myoferlin Redirects Breast Cancer Cell Motility towards Collective Migration

4.  Removing ovaries cuts risk of death in BRCA1/2 carriers

  • Women who inherit mutations in high-risk genes that sharply increase the risk of breast or ovarian cancer can reduce their risk of death by 77% by having their ovaries removed by age 35, a new study shows.
  • The study involved mutations in the genes BRCA1 and BRCA2, which cause 5% to 10% of breast cancers and 15% of ovarian cancers, according to the National Cancer Institute.
  • Women with a mutation in the gene BRCA1 get the clearest benefit to ovary-removal surgery by age 35, says study author Steven Narod, a professor of medicine at the University of Toronto. His study didn’t find any ovarian cancers in women with BRCA2 mutations until age 40. So BRCA2 carriers can likely wait until age 40 for ovarian removal, he says.
  • In some cases, women who had their ovaries removed later learned that they already had ovarian cancer. But because these cancers were generally found early – before they caused symptoms – survival was very high, with 92% of women living at least five years after diagnosis, the study shows.
  • Among women who didn’t have their ovaries removed, and who were diagnosed with ovarian cancer after symptoms appeared, only 35% were alive 10 years later, Narod says.
  • But removing the ovaries at such a young age carries heavy costs in terms of quality of life, says Noah Kauff, director of ovarian cancer screening and prevention at Memorial Sloan Kettering Cancer Center in New York, who wasn’t involved in the study. It puts an end to childbearing and plunges women instantly into menopause, which can cause disruptive symptoms such as hot flashes, while also increasing the long-term risks of heart disease and bone fractures.
  • Researchers considered these increased risks but still found a huge drop in mortality before age 70, Narod says. Researchers didn’t estimate the risk of death after age 70, because by that age, women are at increased risk of death from many causes, Narod says.
  • Kauff says the study may overestimate the benefits from ovarian removal, however. That’s because 60% of the women who had ovary surgery had the organs removed before the study began. Women with very aggressive ovarian cancers, detected only during surgery, would never have made it into the study, he says.
  • Kauff also says he’s concerned the study will scare young women into having surgery before they’re ready. Although BRCA1 mutation carriers who had their ovaries removed between age 40 and 49 had a 3.8% risk of cancer, Kauff notes that their cancers were often curable.
  • The study notes that even surgeries to remove the ovaries and fallopian tubes, which connect the ovaries to the uterus, don’t completely reduce the risk. That’s because ovarian cancer also can occur in the peritoneum, or lining of the abdomen. About 4% of women with BRCA1 mutations developed peritoneal cancer within 20 years of removing their ovaries, the study says. Likewise, women who have double mastectomies have a small risk of developing breast cancer, especially in the small amount of breast tissue under the armpit.
  • “These are tough decisions,” says Friedman, whose group helped doctors recruit patients for the study. “Survival is not the only outcome. Quality of life matters, too.”

5.  Invasive lobular carcinoma may benefit from personalized treatment approach

  • Invasive lobular carcinoma, which is characterized by a unique growth pattern in breast tissue that fails to form a lump, has distinct genetic markers that indicate there may be benefits from drug therapies beyond those typically prescribed for the more common invasive ductal carcinoma.
  • Patients with invasive lobular carcinoma are typically treated through surgical removal of the cancer, followed by chemotherapy or hormone therapy or both, usually with the estrogen-mimicking drug tamoxifen or estrogen-lowering aromatase inhibitors, the same as patients with invasive ductal carcinoma.
  • “However, recent analyses have shown that a subset of patients with lobular carcinoma receive less benefit from adjuvant tamoxifen than patients with ductal carcinoma,” said senior author Steffi Oesterreich, Ph.D., professor at UPCI, a partner with UPMC CancerCenter, and director of education at the Women’s Cancer Research Center. “Our study, the largest of its kind, indicates an issue with the estrogen receptors inside lobular carcinoma cells and points to a potential target for drug therapy in future clinical trials, which we are developing.”

For more information:  The Journal of Cancer Research – doi:10.1158/0008-5472.CAN-13-2779 – Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response.

6.  Tumor-infiltrating lymphocytes predicted outcomes in triple-negative breast cancer

  • High intratumoral and stromal tumor-infiltrating lymphocytes were linked to improved outcomes among patients with triple-negative breast cancer who had residual disease after neoadjuvant chemotherapy, according to results of a retrospective, multicenter study.
  • “The presence of tumor-infiltrating lymphocytes in residual disease after neoadjuvant chemotherapy is associated with better prognosis is triple-negative breast cancer patients,” the researchers wrote. “This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.”

For more information:  Annals of Oncology – 10.1093/annonc/mdt556 – Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

7.  Protein linked to invasive spread of triple-negative breast cancer may lead to targeted therapies

  • Targeted therapy for TNBC is limited by a lack of understanding of the molecular mechanisms behind this form of the disease.
  • Now, Qiang Yu and co-workers at the A*STAR Genome Institute of Singapore, together with scientists from Singapore and the United States, have discovered that a protein known as a protein tyrosine phosphatase—encoded by the UBASH3B gene—is overexpressed in one third of TNBC patients and could form the basis of a targeted therapy for TNBC1.
  • Their results showed that the UBASH3B-encoded protein—a T-cell receptor repressor—was overexpressed in the most invasive TNBC cell lines.
  • “We discovered that UBASH3B modulates the protein expression of the epidermal growth factor receptor, promoting invasion and allowing TNBC to take a stronger hold,” explains Yu. “In addition, UBASH3B is usually inhibited by an anti-invasive microRNA, but this effect is often downregulated in TNBC, which aids protein tyrosine phosphatase overexpression.”
  • The team found that a high level of UBASH3B expression in TNBC patients is directly linked to a poor survival rate. By knocking down UBASH3B in TNBC-affected mice, Yu’s team was able to substantially increase the life expectancy of the mice and reduce their chance of metastasis.
  • Further clarification of TNBC molecular mechanisms is required but Yu is confident that UBASH3B could prove crucial in the development of TNBC-targeted therapies. “UBASH3B could be a potential drug target, and equally it could be used as a biomarker to predict the outcome of TNBC” says Yu. “We will continue to pursue a more clinical validation to verify these approaches.”

For more information:   “Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis.” Proceedings of the National Academy of Sciences USA 110, 11121–11126 (2013).

8.  Trastuzumab-based chemotherapy most effective among HER-2–enriched tumor cancers

  • Researchers in Spain identified as many as four subgroups of HER-2–positive breast cancer, revealing one subtype to be particularly responsive to chemotherapy.
  • “Specifically, we have found that HER-2–positive tumors in the HER-2–enriched subtype have a highly activated HER-2 signaling pathway, thereby making them especially sensitive to anti-HER-2 targeted therapies such as trastuzumab,” Aleix Prat, MD, PhD, principal investigator of Vall d’Hebron Institute of Oncology Translational Genomics Group, said in a press release.

For more information:  Clin Cancer Res. 2014;doi:10.1158/1078-0432.CCR-13-0239

9.  Oncology societies issue guideline on margins for breast-conserving surgery with whole-breast irradiation

  • The American Society for Radiation Oncology and the Society of Surgical Oncology have announced the publication of the consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stage I and stage II invasive breast cancer.
  • The consensus guideline includes eight clinical practice recommendations:
  1. Positive margins, defined as ink on invasive cancer or ductal carcinoma in situ, are associated with at least a two-fold increase in ipsilateral breast tumor recurrence. This increased risk is not nullified by delivery of a boost, delivery of systemic therapy or favorable biology;
  2. Negative margins (no ink on tumor) optimize ipsilateral breast tumor recurrence. Wider margin widths do not significantly lower this risk;
  3. The rates of ipsilateral breast tumor recurrence are reduced with the use of systemic therapy. In the event that a patient does not receive adjuvant systemic therapy, there is no evidence suggesting that margins wider than no ink on tumor are needed;
  4. Margins wider than no ink on tumor are not indicated based on biologic subtype;
  5. The choice of whole-breast irradiation delivery technique, fractionation and boost dose should not be dependent on margin width;
  6. Wider negative margins than no ink on tumor are not indicated for invasive lobular cancer. Classic lobular carcinoma in situ at the margin is not an indication for re-excision.
  7. Young age (≤40 years) is associated with both an increased risk of ipsilateral breast tumor recurrence after breast-conserving therapy and an increased risk of local relapse on the chest wall after mastectomy and is more frequently associated with adverse biologic and pathologic features. There is no evidence that increased margin width nullifies the increased risk of ipsilateral breast tumor recurrence in young patients; and
  8. An extensive intraductal component identifies patients who may have a large residual ductal carcinoma in situ burden after lumpectomy. There is no evidence of an association between increased risk of ipsilateral breast tumor recurrence and extensive intraductal component when margins are negative.

The consensus guideline is available open access online as a PDF document at, and, and will be published in:

  • the March 1 print issue of the International Journal of RadiationOncology*Biology*Physics;
  • the March print issue of Annals of Surgical Oncology; and
  • the March 10 issue of the Journal of Clinical Oncology.

10. Breast-conserving therapy did not increase risk for local recurrence in triple-negative disease

  • Breast-conserving therapy did not increase risk for local recurrence in patients with triple-negative breast cancer, according to results of a prospective database review.
  • Researchers conducted the study to compare the outcomes of breast-conserving therapy in patients with triple-negative breast cancer vs. those with luminal A, luminal B and ERBB2 subtypes.

For more information: AMA Surg. Published online January 01, 2014. doi:10.1001 – Breast-Conserving Therapy for Triple-Negative Breast Cancer


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