MammaPrint Assay Reduces use of Chemotherapy in Breast Cancer Patients

In the American Association for Cancer Research (AACR) meeting 2016, Martine Piccart, MD, PhD, of the Jules Bordet Institute in Brussels, Belgium said that use of the gene assay was associated with a 46% reduction in prescriptions for chemotherapy among the 3,348 high-risk patients and 14% reduction for all 6,648 patients in the study. The meeting coverage was published in the Medpage Today on 22.04.2016.

English: Validation chart for Agendia's MammaPrint Assay, part of the Symphony Breast Cancer Suite (Photo credit: Wikipedia)

Patients at high clinical/pathologic risk but low risk by the 70-gene MammaPrint assay had a 5-year distant metastasis-free survival (DMFS) of 94.4% without chemotherapy versus 95.9% with chemotherapy, a difference that did not reach statistical significance (HR 0.78, 95% CI 0.50-1.21).
In patients with a low clinical risk but high genetic risk, the 5-year DMFS was 95% to 96% with or without chemotherapy.
As compared to standard clincopathological classification, MammaPrint re-stratified 20% of Clinical High Risk patients to Low risk.  97% of this Low Risk patient group which primarily chose to forgo chemotherapy, were disease free at 5 years.
The first ever prospective clinical study for a breast cancer recurrence assay, RASTER (MicroarRAy PrognoSTics in Breast CancER) was published in 2013.
"The MammaPrint FFPE (Formalin Fixed Paraffin Embedded) tissue test has been approved by the FDA."
It confirmed the utility of the MammaPrint (Agendia) 70-gene signature to identify those breast cancer patients that may safely forgo chemotherapy.

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Mutation in BRCA Gene substantially Increases the Risk of Breast Cancer in both Female and Male

An article published in Mail Online about the story of a young lady, who in spite of regular screening for breast cancer, preferring for prophylactic mastectomy before the age of 31, discovered that she is already harboring a 6 cm tumor in her breast. The article can be accessed here.

Emma Cunliffe has mutated BRCA (BReast CAncer) gene that dramatically increases the risk of cancers; breast and ovarian cancer in particular.

Her mother and grandmother both had been diagnosed in their early 30s for breast cancer. Now, she plans to have her ovaries removed after having a family.

Role of BRCA genes:

Faults or breaks develop in the DNAs (Deoxyribonucleic Acid) that house several genes, may be following repeated divisions or other environmental factors like radiation. The primary responsibility of the BRCA gene is to signal for a protein that can repair the defects in the genes in association with some other proteins. Both BRCA 1 and BRCA 2 protein interact with the protein produced by the RAD51 and PALB 2 gene to mend breaks in DNAs.

BRCA 1 gene encodes a nuclear phosphoprotein that acts as a tumour suppressor. The encoded protein combines with other tumour suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination.

Mutated forms of the genes produce a protein that is not perfect; hence, cannot do the repair work. This leaves the cells multiply uncontrollably, without check.

Apart from breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian cancer, prostate cancer, and colon cancer. The BRCA1 gene is located on chromosome 17q21 -- the long (q) arm of chromosome 17 at position 21.

BRCA 2 gene is located on the chromosome 13q12.3; on the long (q) arm of chromosome 13 at position 12.3.

Heredity - autosomal dominant (AD) (Photo credit: Wikipedia)

Risk to Women having mutated BRCA 1 & 2 genes:

A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

·         Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives. By contrast, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years.

These genes also increase breast cancer risk in men. 

·         Ovarian cancer: About 1.4 percent of women in the general population will develop ovarian cancer sometime during their lives. By contrast, 39 percent of women who inherit a harmful BRCA1 mutation and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years.

Types of faulty genes:

The first breast cancer gene faults to be found were BRCA1 and BRCA2.  There are other genes that significantly increase a woman's risk of breast cancer. They are called TP53 and PTEN. Tests are available for the following genes;

·     BRCA1

·     BRCA2

·     TP53

·     PTEN genes

Researchers have found other common genes that can slightly increase a woman's risk of developing breast cancer. No tests are available for these genes yet but they include

·     CASP8

·     FGFR2

·     TNRCP

·     MAP3K1

·     rs4973768

·     LSP1

Rare genes that can also increase breast cancer risk slightly include

·     CHEK2

·     ATM (ataxia telangiectasia mutated)

·     BRIP1

·     PALB2

No individual tests are available for these genes yet.

Who all need to be screened for defective genes?

·         Breast cancer diagnosed before age 50 years

·         Ovarian cancer

·         Cancer in both breasts

·         Both breast and ovarian cancers

·         Multiple breast cancers

·         Two or more primary types of BRCA1- or BRCA2-related cancers in a single family member

·         Cases of male breast cancer

·         Ashkenazi Jewish ethnicity

·         Triple-negative (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) breast cancer

·         Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family

·         Two or more relatives with breast cancer, one under age 50

·         Three or more relatives with breast cancer at any age

·         A previously identified BRCA1 or BRCA2 mutation in the family

In the instant case, MRI could not detect it as it was of a cotton-wool consistency; it was reported.

Recommendation:

In these high risk women;

1.     Breast Self Examination (BSE) should start as age of 20

2.     Clinical Breast Examination (CBE) by a heath care person at the same age

3.      Contrast MRI and Mammogram, both, not anyone, should start from 25 years or 10 years before the age at which the breast cancer in family member is detected; but not before the age of 15.

Contrast MRI and Mammogram both act as complimentary, as MRI is more sensitive, but less specific, gives more unnecessary warnings; Mammography, can even detect some tumors which MRI cannot.

This information is not at all a substitute for the opinion of your consultant.

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Does Your Mammogram Report mentions anything about Dense Breast Parenchyma?

You should not get swayed by your mammogram report that does not mention anything about the density of breast parenchyma, in spite of all normal findings.

Breast implant: Mammographs: Normal breast (left) and cancerous breast (right). (Photo credit: Wikipedia)

According to legislation passed in Connecticut, the radiologist is expected to mention about the density of breast tissue. “Dense parenchyma” that “lowers the sensitivity of mammography”.
where applicable, such report shall include the following notice:
"If your mammogram demonstrates that you have dense breast tissue, which could hide small abnormalities, you might benefit from supplementary screening tests, which can include a breast ultrasound screening or a breast MRI examination, or both, depending on your individual risk factors. A report of your mammography results, which contains information about your breast density, has been sent to your physician's office and you should contact your physician if you have any questions or concerns about this report."
The Legislation can be viewed here.
This legislation was passed because of Nancy Cappello, a 61-year-old Connecticut woman. Her breast cancer had spread to her lymph nodes by the time it was diagnosed, even though she had had normal mammograms every year.
Ms. Cappello, the woman who started the movement to inform patients, began having yearly mammograms at age 40. In 2004, when she was 51, her doctor felt a lump in her breast, only six weeks after a mammogram had looked normal. Even after the lump was detected, mammography still could not find it. Only then, Ms. Cappello was told that she had dense breast tissue. The cancer had already spread to 13 lymph nodes. She needed a mastectomy, chemotherapy, radiation and hormone treatment.
Mammograms are scored on a five-point scale, using the following American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories:

1. Negative;
2. Benign finding;
3. Probably benign finding, short follow-up interval suggested;
4. Suspicious abnormality, biopsy should be considered; and
5. Highly suggestive of malignancy.

After this, the density of breast tissue has to be mentioned. Laws requiring disclosure of density have been passed in Connecticut, Texas and Virginia, and most recently in California and New York.
“Dense” breasts have a relatively high proportion of glandular or connective tissue, which blocks X-rays used in mammography. Non-dense breasts have more fat through which X-rays penetrate easily.
Over all, about 40percent of women who have mammograms have dense breast tissue. It is not abnormal, just one of nature’s variations. Younger women are more likely to have dense tissue, but as many as 25 percent of older women have it. Density cannot be judged by touch; it shows up only on mammograms.
In dense breast tissue, there is chance that abnormality may remain unnoticed.  Something like, trying to see ice through ground glass. However,mammogram is gold standard, should not be ignored.
If it is a dense parenchyma, there is option for ultrasonogram (USG) and magnetic resonance imaging (MRI). USG and MRI are more sensitive than mammogram, but problem is that more often those give false positive results. False positivity may lead to unnecessary anxiety in patient and warrant more interventions like biopsy.
However, those are useful tool in case of dense breast parenchyma and indicated in case, there exist the risk factors for breast cancer, like strong family history and BRCA 1 or 2 mutation etc..
MRI may be used in women for evaluating;

• The integrity of silicone breast implants,
• Assessing cancers associated with silicon breast implant
• Assessing palpable masses following surgery or radiation therapy,
• Assessing for occult breast cancer in patients with axillary nodal    metastasis found in mammogram or USG,
• Preoperative planning for some patients with known breast cancer.
• It has been promoted as a screening test for breast cancer among women at elevated risk of breast cancer based on BRCA1/2 mutation carriers, a    strong family history of breast cancer, or several genetic syndromes such as Li-Fraumeni or Cowden disease.

Mammography is still the "gold standard" for the detection of breast cancers and the first screening test to be undertaken. Very importantly, it allows for the detection of microcalcifications which may sometimes be the only sign of a very early breast cancer. Microcalcifications are not visible on other types of imaging studies. Digital and 3D Mammograms are more sensitive than screen/film mammogram. The mammogram also helps determine the need for additional studies, such as MRI or sonography.
That is why your radiologist must mention about density of breast parenchyma, if not, you should ask for it.

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Candidates for Tamoxifen Therapy in Breast Cancer may Benefit from CYP2D6 Blood Test for the Effectiveness of the Therapy

Candidates for tamoxifen therapy suffering from breast cancer may benefit from a blood test for CYP2D6 to know whether the therapy will be very effective in them.
For nearly a decade, breast cancer researchers studying the hormone therapy tamoxifen have been divided as to whether genetic differences in a liver enzyme affect the drug's effectiveness and the likelihood breast cancer recurrence.
Researchers from the Mayo Clinic Cancer Center and the Austrian Breast and Colorectal Cancer Study Group provide evidence that genetic differences in the enzyme CYP2D6 may play a key role to determine which patient is going to get best out of the therapy.

Crystallography of 4-hydroxytamoxifen (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (cyan ribbon). PDB 3ERT; Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (December 1998). "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell 95 (7) : 927–37. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847. (Photo credit: Wikipedia)

Tamoxifen is usually prescribed to the patients positive for Estrogen Receptor (ER +ve) as a hormonal manipulation therapy. Tamoxifen itself is a pro-drug, having relatively little affinity for its target protein, the estrogen receptor.
It is metabolised in the liver by the enzyme cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen).
These metabolites, especially the endoxifen has a greater affinity for the ER protein and competitively blocks the binding of the hormone estrogen that facilitates the tumour growth.
Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, that is why it is cytostatic rather than cytocidal.
Multiple investigations have identified genetic variants of CYP2D6 that can  affect its activity, which in turn affects the metabolism of tamoxifen. Where, there is no effective conversion of the pro-drug to its active form that may lead to a worse clinical outcome.
Geno typing, therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes.
Recent studies suggest that taking the selective serotonin re-uptake inhibitors (SSRIs) antidepressants; paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft), can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into the active form; endoxifen.
Researchers are now working with the National Cancer Institute to develop endoxifen as an alternative to tamoxifen. If women can be given endoxifen, the active part of tamoxifen, it won't matter how tamoxifen gets metabolized.

Related articles

• Biomarker Of Tamoxifen Resistance In Breast Cancer Identified
• Side Effects of Tamoxifen?

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Patients of HER2 Negative Breast Cancer may Benefit from Drugs Used for HER2 Positive Breast Cancer

Until recently, no targeted treatment was available for HER2 negative breast cancers, those are negative for Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor (HER2).

A multicenter study led by researchers at UC Davis describes new, paradoxical characteristics of the most common type of breast cancer. The findings shed light on how the disease can evade treatment.

HER2-positive breast cancers are routinely treated with drugs that target the HER2 protein, such as Herceptin (Trastuzumab) with good results. However, until recently, there has been little reason to administer these targeted treatments to patients with HER2-negative cancer.

Now such HER2-negative breast cancers are being treated effectively with anti-HER2 treatments. The mechanism was not clearly understood.

The research, led by Jian Jian Li, director of translational research in the UC Davis Department of Radiation Oncology, examined breast tumors previously thought to lack the HER2 protein, which, when over-expressed, is associated with disease recurrence.

Researchers, rather found a small groups of aggressive, treatment-resistant HER2-positive breast cancer stem cells (BCSCs in such tumors.

Breast cancers differ on the cellular level. Whether a tumor contains HER2, an estrogen receptor protein, a progesterone receptor protein or all three or none can have an enormous impact on the tumor's aggressiveness, the patient's overall prognosis and treatment choices.

They also analyzed the stem cells for CD44 and CD24, cell surface proteins that indicate cancer aggressiveness and act as BCSC markers.

The team found that the HER2-positive, CD44 positive, CD24 negative/low BCSCs were more aggressive and highly resistant to radiotherapy. These characteristics were significantly reduced by Herceptin or short interfering RNA.

HER2 and CD44 positive BCSCs were found in 57.1 percent of primary tumors and 84.6 percent of recurrent tumors.

In addition to identifying this previously hidden group of HER2-positive stem cells, further examination provided new insights into how these BCSCs maintain their resistance to treatment.

A complex network of proteins, including HER2 and STAT3, modulate metastasis, programmed cell death and other functions. As a result, these cells survive the gamut of traditional anti-cancer therapies.

This research provides detailed confirmation that HER2 treatment can potentially improve outcomes in HER2-negative breast cancers.

The original article, published in the Medicalxpress can be accessed here.

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Phase Contrast Tomography for 3D Image of Breast cancer

Conventionally, breast cancer imaging is done by mammography that gives a 2D view. CT of breast can give good quality image but requires a larger dose of x-rays.
To get good 3D image with less radiation, Miao's international colleagues in collaboration with the European Synchrotron Radiation Facility in France and Germany's Ludwig Maximilians University, used a special detection method known as phase contrast tomography to X-ray a human breast from multiple angles.
They then applied equally sloped tomography, or EST -- a breakthrough computing algorithm developed by Miao's UCLA team that enables high-quality image-reconstruction -- to 512 of these images to produce 3-D images of the breast at a higher resolution than ever before. The process required less radiation than a mammogram.

Related articles

• Breakthrough images tumors in 3-D with less radiation
• New X-ray breast cancer imaging possible with 25 times reduced radiation dose

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Breast Implants may Hide Cancer and are Associated with Rare Lymphoma

Approximately 25,000 women in the UK go for breast implants in a year. A study was conducted on  40,000 women with implants, of whom 409 got diagnosed for late stage breast cancer.
Researchers in Canada say women with boob jobs are three times more likely to be diagnosed with advanced cancer. Their chances of dying from it go up by 30%.

As silicon implants are radio-opaque, so cancerous tissue may remain hidden from getting imaged in mammograms. So, those grow to advanced stage to get detected.

Breast implant: Mammographs: Normal breast (left) and cancerous breast (right). (Photo credit: Wikipedia)

Therefore, taking X-rays from different angles can address this.

A study, published online by the journal Plastic and Reconstructive Surgery, also brings to light that there is an association between anaplastic large cell lymphoma (ALCL) and breast implant.

Concerns about an association between ALCL and breast implants were first raised in 1996 when doctors published a report describing a woman with implants who had developed the cancer in tissue located next to one of her implants.

Since that time, similar reports have been published, estimating that about one to three cases would be diagnosed annually per 1 million women with implants.

It is reassuring that ALCL takes a slow course and can be controlled by surgical removal of the implant and surrounding capsule.

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