Best of Breast: news for week ending 19 December 2014

A summary of medical developments in cancer and breast cancer, collated from Google Alerts, for the week ending 19 December 2014.

Venn

Tamoxifen.

 

I still have a lot of catching up to do, and I’ve just realised that the news feeds are full of the 2014 San Antonio Breast Cancer Symposium – help!

I know I should rejoice because the Symposium is full of researchers jostling to show off their latest “cures”, but after so many years of following the Symposium (and other symposiums) I’ve come to realise that they are about shoot-outs between different types of chemotherapy, and that the supposed breakthroughs haven’t really filtered through to mainstream/commercial/ affordable treatments.

I open with CYP2D6 testing as a marker for how effectively the body can metabolise tamoxifen.

Tamoxifen [Endoxifen] has long been the de facto treatment for (pre-menopausal) women with estrogen-positive breast cancer, it’s been touted as a preventative against recurrences.

However, what they don’t tell us is that tamoxifen doesn’t always work, or it may work only partially.  Tamoxifen is metabolized by the human body, via the CYP2D6 gene, into endoxifen which is the active metabolite.  If there are variants in the CYP2D6 gene, then this means that tamoxifen will not be effectively metabolised.

The test for CYP2D6 can be obtained in the US by the Mayo Clinic (Cytochrome P450 2D6 Genotype for Tamoxifen Hormonal Therapy) and in the UK by Roche (Roche AmpliChip® CYP450 Test).  See also information  on:  http://emedicine.medscape.com/article/1762071-overview

It is well worth getting if you want answers if you think tamoxifen isn’t working for you.  However, the solution, as some research seems to suggest, is to increase the dose of tamoxifen, or to switch off the ovaries [chemically or via ablation] and take more hormonal suppressors.

The second article is about a 20-year study which seemed to show that although tamoxifen prevented incidences of breast cancer, this did not affect overall mortality, and in fact led to an increase in ER-negative tumours after 10 years, and a 45% increase in endometrial cancer.  It seems to be saying:  yes, there’s less chance of you dying of breast cancer, but you’re still going to die of something else

(Damned if you do and damned if you don’t.)

The third article seems to offer an alternative to suppressing estrogen: by targetting androgen receptors instead.

1.  CYP2D6 Remains Important Biomarker of Tamoxifen Effectiveness

http://medicalresearch.com/cancer-_-oncology/breast-cancer/breast_cancer_biomarker_of_tamoxifen_effectivenss/9719/

  • There has been conflicting data with regard to the importance of tamoxifen metabolism as measured by CYP2D6 genetic variation.
  • Two large “negative” studies were reported simultaneously in 2012 and these were referenced by guidelines that CYP2D6 should not be used to select hormonal therapy.
  • Findings demonstrated that these studies were flawed in part based on analytical validity issues.
  • In short, the use of tumor tissue to derive CYP2D6 germline genotype leads to genotyping error in up to 45% of samples.
  • Until prospective trials are available, guidelines regarding the use of CYP2D6 genotype should be derived from studies without evidence for genotyping error, and these studies show that CYP2D6 is an important marker of tamoxifen effectiveness.

For more information: JNCI J Natl Cancer Inst, Volume 107, Issue 2, 10.1093/jnci/dju401, Loss of Heterozygosity at the CYP2D6 Locus in Breast Cancer: Implications for Germline Pharmacogenetic Studies

2.  Twenty years after initiating preventive tamoxifen, less breast cancer but no survival benefit

http://www.oncologypractice.com/the-oncology-report/home/article/20-years-after-initiating-preventive-tamoxifen-less-breast-cancer-but-no-survival-benefit/5fb9c2b8699e21598180f929f0751720.html

  • Five years of tamoxifen provided 20 years of breast cancer prevention to some at-risk women who took it prophylactically.
  • However, their 20-year all-cause mortality was no different from those taking placebo (182 vs. 166 deaths), nor was their mortality from breast cancer (31 vs. 26, respectively).
  • IBIS-1 was first reported in 2002, when 4-year follow-up found a 32% reduction in breast cancer risk associated with tamoxifen.
  • It also found a significant increase in deaths among that group (25 vs.11 in placebo), many of which were attributable to more endometrial cancer (11 vs. 5).

For more information:  2014 San Antonio Breast Cancer Symposium. Abstract S3-07. Presented December 11, 2014.  6 year long-term follow-up of the IBIS-I breast cancer prevention trial.   Also:  Lancet Oncol. 2015 Jan;16(1):67-75. doi: 10.1016/S1470-2045(14)71171-4. Epub 2014 Dec 11.  Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.

3.  Three Different Studies Target Androgen Receptors in Breast Cancer

http://breastcancer-news.com/2014/12/17/three-different-studies-target-androgen-receptors-breast-cancer/

  • During the 2014 San Antonio Breast Cancer Symposium, three studies presented by researchers from the University of Colorado Cancer Center showed the outcomes of androgen receptor blockade in breast cancer.
  • The first study demonstrated that this blockade lowers the growth of estrogen-positive (ER+) breast cancers
  • The second study showed that triple-negative breast cancers (TNBCs) that should not be sensitive to hormonal stimuli and have a low prognosis, rely on androgen receptor activation.
  • In the third study, researchers found that blocking androgen receptors together with HER2 or mTOR had an enhanced effect, resulting in increased cancer cell death.
  • Past research has showed that the existence of androgen receptors on breast cancer cells could be a determining factor in tamoxifen resistance.
  • One study showed that upon androgen receptor activation, there is a receptor re-localization into the cell nucleus, which allows breast cancer cells to respond to estrogen stimuli.
  • Researchers found that enzalutamide, a drug that is capable of blocking this nuclear localization, can also prevent estrogen binding, reducing the proliferation and expansion of estrogen-dependent breast cancer cells.

For more information:  2014 San Antonio Breast Cancer Symposium,  abstracts, Inhibiting androgen receptor nuclear localization decreases estrogen receptor (ER) activity and tumor growth in ER+ breast cancer, Androgen receptor expression in triple negative breast cancer, Investigation into the oncogenic potential of the androgen receptor in aromatase inhibitor resistant breast cancer

4.  Cancer Rates Higher in Type 1 and Type 2 Diabetes

http://www.webmd.com/cancer/news/20141216/diabetes-cancer-rates

  • People with type 1 or type 2 diabetes are diagnosed with more of some types of cancer — and are more likely to die from cancer — than people without diabetes.
  • The researchers say that close follow-up, given right after a diabetes diagnosis,  might partly explain the increased cancer risk seen.
  • But these factors “do not explain increased risks 2 years following diabetes diagnosis, particularly for cancers of the pancreas, liver, kidney, and endometrium.”
  • It’s not likely that insulin is the driving force behind the cancers, the researchers say.
  • Instead, they suggest that high blood sugar, which doctors call hyperglycemia, may be a contributing factor.
  • Based on the findings, the researchers say, people with diabetes should get screened for cancer, which could help doctors treat cases early and lessen premature deaths due to cancer.

For more information:  Diabetes Care, doi:10.2337/dc14-1996, Cancer Risk Among People With Type 1 and Type 2 Diabetes: Disentangling True Associations, Detection Bias, and Reverse Causation

5.  Zinc blood test could lead to early diagnosis of breast cancer

http://pubs.rsc.org/en/content/articlelanding/2015/mt/c4mt00260a#!divAbstract

  • An early diagnostic biomarker for breast cancer is essential to improve outcome.
  • High precision isotopic analysis, originating in Earth sciences, can detect very small shifts in metal pathways.
  • For the first time, the natural intrinsic Zn isotopic compositions of various tissues in breast cancer patients and controls were determined.
  • Breast cancer tumours were found to have a significantly lighter Zn isotopic composition than the blood, serum and healthy breast tissue in both groups.
  • The Zn isotopic lightness in tumours suggests that sulphur rich metallothionein dominates the isotopic selectivity of a breast tissue cell, rather than Zn-specific proteins.

For more information:  Metallomics, 2015,7, 112-117, DOI: 10.1039/ C4MT00260A, Zinc isotopic compositions of breast cancer tissue

6.  How Calling Cancer a ‘Fight’ or ‘Battle’ Can Harm Patients

http://time.com/3636102/fighting-cancer/

  • Using hostile, warlike metaphors to describe cancer may make patients less likely to take steps toward certain treatments, new research suggests.
  • The study found that patients are less likely to engage in important limiting behaviors, like reducing smoking and cutting back on red meat, when researchers associated cancer with words like “hostile” and “fight.”
  • In fact, the study shows that war metaphors do not make patients any more likely to seek more aggressive treatment.
  • In earlier research, investigators found that war metaphors can lead to feelings of guilt and failure in patients who die of cancer, even though they have little control managing it.
  • “Blame is being put on the patient, and there’s almost a sense that, if you are dying, you must have given up and not have fought hard enough.”

For more information:  Personality and Social Psychology Bulletin,  doi:10.1177/0146167214557006, The War on Prevention:  Bellicose Cancer Metaphors Hurt (Some) Prevention Intentions

7.  Shape of antibody makes a difference in fighting cancer

http://www.medicalnewstoday.com/articles/287018.php

  • Researchers from the University of Southampton in the UK found a particular naturally occurring antibody called IgG2 is much more effective at stimulating the immune system to fight cancer than other types of antibody.
  • IgG2 is unique among antibodies because it can work on its own without the help of other immune cells. This makes it more active and effective in all tissue types.
  • A version of the antibody – IgG2B – is particularly effective at stimulating antitumor immunity because it has what is known as a “locked B structure.”
  • The team also found they could engineer antibodies to have this particular shape – thus opening the door to making stronger immune stimulators than previous drugs.

For more information:  Cancer Cell, doi:10.1016/j.ccell.2014.11.001, published online 11 December 2014, Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies

8.  Scientists discover protein that stops cancer developing

http://www.heraldscotland.com/news/home-news/scientists-discover-protein-that-stops-cancer-developing.114622632

  • A protein called HIRA, which prevents cancer developing could eventually be used to create new cancer treatments.
  • As cancer is the uncontrolled growth of cells, the discovery of this protein is relevant to all forms of cancer and not just those related to the skin.

For more information:  Genes and Development,  2014.  28: 2712-2725,  doi:10.1101/gad.247528.114, HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

9.  Hormone-unrelated breast cancer death rate lowered by reducing dietary fat

http://www.medicalnewstoday.com/articles/286945.php
  • Reducing dietary fat intake for at least 5 years after diagnosis could help improve survival rates for early-stage breast cancer patients with hormone-unrelated breast cancer, according to a new study.
  • “Overall, while the death rate was somewhat lower in the intervention group compared with control group (13.6% versus 17%, respectively), the difference was not statistically significant.
    However, in exploratory subgroup analyses, in women with estrogen receptor (ER)-negative cancers, a 36%, statistically significant reduction in deaths was seen in women in the intervention group.”
  • Death rate reduction was found by the researchers to be even more significant – at 56% – in women whose breast cancer was both ER-negative and progesterone receptor (PR)-negative.

For more information:  San Antonio Breast Cancer Symposium 2014,  Abstract S5-08: Final survival analysis from the randomized Women’s Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy

10.  ESR1-DAB2 fusion gene mutation could help explain how breast cancer spreads

  • http://medicalxpress.com/news/2014-12-newly-identified-gene-mutation-breast-cancer.html
  • Researchers sequenced frozen breast tumour samples from six patients, beginning with the primary tumor when the cancer was first diagnosed through the progression of metastatic disease.
  • Using multiple sequencing techniques, the team identified a new gene (ESR1-DAB2) created by two separate genes that fused together as a result of unstable DNA.
  • This fusion gene was identified in a metastatic tumor sample and is believed to play a part in the spread of the original breast cancer.

For more information:  San Antonio Breast Cancer Symp0sium 2014, Identification of base pair mutations and structural rearrangements acquired in breast cancer metastases including a novel hyperactive ESR1-DAB2 fusion gene specifically in hormone-resistant recurrence

11.  Capecitabine monotherapy ineffective in elderly early breast cancer patients

http://www.cancernetwork.com/sabcs-2014/capecitabine-ineffective-elderly-early-breast-cancer-patients#sthash.SzQ5Bcb5.dpuf

  • The use of adjuvant capecitabine in elderly patients with moderate- to high-risk early breast cancer resulted in no improvement in disease-free survival, according to a study presented at the 2014 San Antonio Breast Cancer Symposium.
  • The phase III ICE study tested ibandronate, a bisphosphonate, with or without capecitabine in women aged 65 years or older.
  • Capecitabine was chosen because it is associated with fewer side effects than conventional chemotherapy using anthracyclines or taxanes.
  • In addition, in 2004, when the trial was started, there was evidence that the use of bisphosphonates in the elderly might cause breast cancer relapse.

For more information:  2014 San Antonio Breast Cancer Symposium,  Abstract S3-04The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer

Fulvestrant 500 mg significantly improved overall survival compared with anastrozole, among women with treatment-naive, advanced, hormone receptor-positive breast cancer, according to data from the phase II FIRST trial presented at the 2014 San Antonio Breast Cancer Symposium (SABCS).

  • Fulvestrant, a selective estrogen–receptor downregulator, is given via intramuscular injection once a month.
  • The drug is approved for use in the second-line setting for metastatic hormone receptor–positive breast cancer that has progressed on first-line hormonal therapy.
  • It is not approved as adjuvant therapy, even though it is considered the most potent antiendocrine therapy available.

For more information:  San Antonio Breast Cancer Symposium 2014. Abstract S6-04, “Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the phase II “first” study.”

13.  Nab-Paclitaxel Wins Neoadjuvant Taxane Battle in Breast Cancer Trial

http://www.medpagetoday.com/MeetingCoverage/SABCS/49120

  • A comparison of two paclitaxels resulted in a clear win for nab-paclitaxel (Abraxane) as neoadjuvant therapy for early breast cancer.
  • Treatment with nab (nanoparticle albumin-bound)-paclitaxel resulted in a pathologic complete response (pCR) of 38% compared with 29% for solvent-based paclitaxel.
  • Patients received weekly taxane therapy for 12 weeks, followed by 12 weeks of epirubicin and cyclophosphamide.

For more information:  Cancer Res May 1, 2015 75;S2-07, doi: 10.1158/1538-7445.SABCS14-S2-07, Abstract S2-07: A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69

14.  Musashi proteins drive cancer cells to change states

https://newsoffice.mit.edu/2014/proteins-make-cancer-cells-change-states-1215

  • A new study implicates a family of RNA-binding proteins in the regulation of cancer, particularly in a subtype of breast cancer.
  • These proteins, known as Musashi proteins, can force cells into a state associated with increased proliferation.
  • Biologists have previously found that this kind of transformation, which often occurs in cancer cells as well as during embryonic development, is controlled by transcription factors — proteins that turn genes on and off.
  • However, the new research reveals that RNA-binding proteins also play an important role.
  • Human cells have about 500 different RNA-binding proteins, which influence gene expression by regulating messenger RNA, the molecule that carries DNA’s instructions to the rest of the cell.
  • RNA-binding proteins have traditionally been used to identify neural stem cells, in which they are very abundant.
  • They have also been found in tumors, including in glioblastoma, a very aggressive form of brain cancer.
  • Musashi proteins are most highly expressed in a type of breast tumors called luminal B tumors, which are not metastatic but are aggressive and fast-growing.
  • When the researchers knocked down Musashi proteins in breast cancer cells grown in the lab, the cells were forced out of the epithelial state.
  • Also, if the proteins were artificially boosted in mesenchymal cells, the cells transitioned to an epithelial state.
  • This suggests that Musashi proteins are responsible for maintaining cancer cells in a proliferative, epithelial state.

For more information:  dspace@mit, http://dspace.mit.edu/handle/1721.1/ 92373:  Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state

15.  Molecular Link Discovered Between Prostate and Breast Cancer, Suggesting New Treatment Approach for Men’s Tumor

http://weill.cornell.edu/news/news/2014/12/molecular-link-discovered-between-prostate-and-breast-cancer-chakravarty-sboner-rubin.html

  • Prostate cancer can be driven by the same estrogen receptor responsible for the most common form of breast cancer.
  • Men use both hormones — androgen and estrogen — and their levels are physiologically balanced in early and mid-life.
  • But as men age, the levels of androgen go down and estrogen rises, for reasons that are not understood.
  • The research team discovered that estrogen receptors hijack the androgen-signaling pathway to promote prostate cancer growth.

For more information:  Nature Communications 5, Article number: 5383doi: 10.1038/ncomms6383, The ​oestrogen receptor alpha-regulated lncRNA ​NEAT1 is a critical modulator of prostate cancer

16.  New drug, Palbociclib, holds promise for women with advanced breast cancer

http://www.examiner.com/article/new-drug-holds-promise-for-women-with-advanced-breast-cancer

  • The experimental drug palbociclib, discovered and being developed by Pfizer Inc., doubled the amount of time women were under treatment without their advanced breast cancer worsening.
  • Palbociclib targets an important family of proteins (CDK4/6) responsible for cell growth by preventing them from replicating.
  • The patients were given a combination of the standard anti-estrogen treatment letrozole plus palbociclib, compared to letrozole alone.
  • The investigators found that preclinical work testing the drug on human breast cancer cells growing in the laboratory showed very encouraging activity, specifically against ER+ cancer cells.
  • The drug does not have side-effects that commonly occur with traditional chemotherapy, such as infections; however, it does lower the white blood cell count, which was very manageable.
  • The FDA has granted palbociclib “Breakthrough Therapy” status.

For more information:  Lancet Oncology, Volume 16, No. 1, CDK4/6 inhibitors in luminal breast cancer

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