Data Visualization In The Gem Dataset
For visualization of the high-dimensional data in our analyses, we produced smoothed versions of scatterplots with colors representative of the data densities. The smoothed scatterplots were generated using the smoothScatter function in the graphics package in R. For our plotting parameters, we used 250 bins for density estimation. The densities were represented by the following sequence of colors: white > beige > gray > black > orange > red.
Oestrogen Receptor Positive Breast Cancer
Oestrogen is a hormone that plays an important role in the female reproductive system.
Sometimes breast cancer cells contain oestrogen receptors. This is called oestrogen receptor positive or ER positive breast cancer, often shortened to ER+.
When oestrogen receptors are found in breast cancer cells, this can help the breast cancer to grow.
All invasive breast cancers are tested for oestrogen receptors using tissue from a biopsy or after surgery. Invasive breast cancer is cancer that has the potential to spread.
Why Is Knowing Hormone Receptor Status Important
Knowing the hormone receptor status of your cancer helps doctors decide how to treat it. If your cancer has one or both of these hormone receptors, hormone therapy drugs can be used to either lower estrogen levels or stop estrogen from acting on breast cancer cells. This kind of treatment is helpful for hormone receptor-positive breast cancers, but it doesnt work on tumors that are hormone receptor-negative .
All invasive breast cancers should be tested for both of these hormone receptors either on the biopsy sample or when the tumor is removed with surgery. About 3 of 4 breast cancers have at least one of these receptors. This percentage is higher in older women than in younger women. DCIS should also be checked for hormone receptors.
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Gene Expression Microarray Cohort
We integrated data from a total of 20 previously published gene expression microarray datasets. Nineteen of the datasets were initially provided as supporting material in , and the 20th dataset comes from The Cancer Genome Atlas breast cancer cohort . To access the TCGA data, we downloaded the Level 3 loess normalized Agilent microarray mRNA expression data from the Broad Institutes Genome Data Analysis Center. None of the public gene expression microarray data used in this study required additional consent to analyze or publish results obtained from the data. Further description of the datasets is provided in Additional file : Table S1.
Estrogen And Progesterone Receptor Testing For Breast Cancer
To help doctors give their patients the best possible care, the American Society of Clinical Oncology and the College of American Pathologists developed evidence-based guidelines to improve the accuracy of testing for estrogen and progesterone receptors for breast cancer. This guide for patients is based on ASCO’s and CAP’s 2020 updated recommendations.
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Chemicals And Additives To Avoid
Many chemicals used in agriculture, body care products, food packaging and plastic water bottles are estrogenic, called xenoestrogens or estrogen mimics. In addition to binding with estrogen receptors, these toxins are fat soluble, so they tend to accumulate in fat cells. We know that breast tissue has a high concentration of fat, particularly after menopause. Studies have shown that breast milk often contains dangerous levels of these chemicals. Reduce exposure by avoiding plastic food and beverage containers, canned foods, and body products with these common chemicals. For a list of chemicals to avoid, visit the Environmental Working Group site.
What About The Pill And Breast Cancer Risk
Youre probably wondering, if increased exposure to estrogen can raise your risk for breast cancer, what about the pill? Is it a risk factor for breast cancer?
Studies are a bit mixed and therefore inconclusive, but not surprisingly, there does seem to be somewhat of an increased risk for breast cancer in women who use the pill. An early study that examined more than 50 studies on the pill found that women who were currently taking the pill, or even those that took the pill in the past ten years, had a slightly higher risk of breast cancer diagnosis. This risk returned to normal ten years after stopping oral contraceptives.
It may also be that once again, the balance of estrogen with other hormones like progesterone and testosterone is the real reason oral contraceptives might increase the risk.
The bottom line is this: while we don’t have a high-quality smoking gun study showing conclusively that birth control will increase your risk of breast cancer, the mixed results are still reason for caution.
Taking a synthetic hormone pill disrupts your bodys ability to regulate levels on its own, so it stands to reason that at least some of the time, for some women, using hormonal birth control could contribute to breast cancer risk.
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Estrogen Exposure Over Time Is Linked To Breast Cancer
The longer your body is exposed to estrogen throughout your life, the more it appears to increase your risk for estrogen-related breast cancer. This helps explain why most breast cancer diagnoses occur later in life, after a lifetime of exposure to estrogen.
But it gets more interesting. Even though breast cancer risk generally increases as you get older, if you start your period later in life , your risk goes down simply because you had a few extra years without estrogen. The opposite seems true for women who go through menopause later, as more years of estrogen exposure may actually increase the risk for breast cancer.
See the connection? More estrogen equals more risk, according to current research.
Treatment For Er Positive Breast Cancer
If your breast cancer is ER positive, you may be offered hormone therapy.
A number of hormone therapies work in different ways to block the effect of oestrogen or reduce the amount of oestrogen in the body.
It may be given to:
- Reduce the risk of breast cancer coming back after surgery
- Reduce the size of the cancer or slow down its growth
- Treat breast cancer that has come back or spread
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Proteins For Targeted Cancer Drugs
Testing cancer cells for particular proteins can help to show whether targeted drug treatments might work for your breast cancer.
Targeted cancer drugs are treatments that change the way cells work and help the body to control the growth of cancer.
Some breast cancers have large amounts of a protein called HER2 receptor . They are called HER2 positive breast cancers. About 15 out of every 100 women with early breast cancer have HER2 positive cancer.
Targeted cancer drugs such as trastuzumab can work well for this type of breast cancer. These drugs attach to the HER2 protein and stop the cells growing and dividing.
Phytoestrogens And Soy: The Debate
Phytoestrogens are compounds that have a mild estrogenic effect and are found in whole grains, nuts and seeds, and many other botanicals, fruits and vegetables. These foods are associated with a reduced risk of breast cancer as well as reduced cancer reoccurrence.
The controversy becomes heated in the debate over soy-containing foods. This issue is complex, with some studies showing that eating soy early in life can reduce breast cancer risk. On the other hand, the consumption of concentrated soy extracts showed increased proliferation of breast cancer cells. Finally, other studies show a protective or neutral effect from whole soy foods.
My recommendation for soy is to eat whole soy foods in moderation no more than several servings per week, preferably fermented soy foods such as miso or tempeh. Avoid soy protein isolates and supplements containing concentrated soy isoflavones.
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Gene Expression Profiling Data Scaling And Merging
The datasets used in our study were generated using diverse microarray platforms and originating from different laboratories. We used normalized log2 for single-channel platforms and log2 in dual-channel platforms. Hybridization probes were mapped to Entrez Gene ID. When multiple probes mapped to the same GeneID, we used the probe with the highest variance in the dataset under study. We scaled and centered expression values for each gene to have a mean of zero and standard deviation of one in the dataset, prior to merging the data from the different datasets. The complete dataset contains data on 4,111 patients . For the genome-wide analyses, we limited the analysis to the 3,666 patients with valid data from at least 80% of the genes.
Conflict Of Interest Statement
JS sat on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and he Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Hormone Receptor Status And Hormone Therapy
Hormone receptor-positive breast cancers can be treated with hormone therapies.
Hormone therapy drugs include tamoxifen and the aromatase inhibitors, anastrozole , letrozole and exemestane . Ovarian suppression, with surgery or drug therapy, is also a hormone therapy.
Hormone receptor-negative breast cancers are not treated with hormone therapies because they dont have hormone receptors.
Learn about hormone therapy for the treatment of metastatic breast cancers.
Diet And Breast Cancer
Because the role of diet in breast cancer survival is not fully understood, common nutrition advice is based on what is known to prevent breast cancer â and these guidelines aren’t specific to cancer type. In fact, nutrition advice for breast cancer prevention closely matches the breast cancer survivorship guidelines, published in December 2015 by the ACS and the American Society of Clinical Oncology.
These recommendations encourage survivors to consume a diet that emphasizes vegetables, fruits, whole grains and legumes, while limiting alcohol and saturated fat. These guidelines are not specific to cancer type or ER status, although people who have estrogen-dependent cancer may respond well to these recommendations.
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What Types Of Hormone Therapy Are Used For Breast Cancer
Several strategies are used to treat hormone-sensitive breast cancer:
Blocking ovarian function: Because the ovaries are the main source of estrogen in premenopausal women, estrogen levels in these women can be reduced by eliminating or suppressing ovarian function. Blocking ovarian function is called ovarian ablation.
Ovarian ablation can be done surgically in an operation to remove the ovaries or by treatment with radiation. This type of ovarian ablation is usually permanent.
Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called gonadotropin-releasing hormone agonists, which are also known as luteinizing hormone-releasing hormone agonists. By mimicking GnRH, these medicines interfere with signals that stimulate the ovaries to produce estrogen.
Estrogen and progesterone production in premenopausal women. Drawing shows that in premenopausal women, estrogen and progesterone production by the ovaries is regulated by luteinizing hormone and luteinizing hormone-releasing hormone . The hypothalamus releases LHRH, which then causes the pituitary gland to make and secrete LH and follicle-stimulating hormone . LH and FSH cause the ovaries to make estrogen and progesterone, which act on the endometrium .
Examples of ovarian suppression drugs are goserelin and leuprolide .
Blocking estrogens effects: Several types of drugs interfere with estrogens ability to stimulate the growth of breast cancer cells:
What This Means For Patients
Because the results of ER and PR testing can make a difference in a persons treatment and chance of recurrence, it’s important that these tests are accurate. This guideline was developed to help both doctors and laboratories know how to improve the accuracy of ER and PR testing for those with breast cancer. Understanding the ER/PR status of the primary tumor and any distant or recurrent tumors can help doctors make sure that patients receive the appropriate treatment and avoid side effects of a treatment that may not work. Use this guideline to talk with your doctor about the accuracy of your ER and PR test results and what that means for your treatment.
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Are Soy And Flaxseeds Ok
Soy contains phytoestrogens, or plant-based estrogens, which has raised concerns regarding soy’s role in the development of breast cancer however, whole soy products, such as tofu, edamame or soy milk, have been shown to reduce the risk of breast cancer, including ER-positive cancers. This plant protein is also considered a healthy choice for breast cancer survivors.
In fact, a 2010 study from JAMA of more than 5,000 women living in China linked regular, whole soy intake to a reduced recurrence of all breast cancer types. However, isolated soy â found in supplements, soy powder or processed foods â should not be emphasized, as these foods have not been shown to be protective.
Flaxseeds are rich in lignans, a phytoestrogen, and also a good source of omega-3 fats and dietary fiber. Animal studies have shown that components of flaxseed can reduce tumor size and inhibit the growth of ER-positive and ER-negative breast cancer cells and that foods that contain lignan, such as flaxseed, may help decrease breast cancer risk, according to the American Institute for Cancer Research.
Although incorporating small amounts of flaxseed into a healthy diet is encouraged, inadequate human research is available to recommend large amounts of flaxseed, or flaxseed supplements, as a therapy for breast cancer.
D Combination Of Cdk4/6 With Pi3k/akt/mtor
The remarkable results observed with CDK4/6 inhibitors has been very well-received and approved by the FDA. However, a large number of ER+ BC patients continue to experience relapse and recurrence . There is a complex crosstalk between ER+ BC, constitutive PI3K activation and the CDK4/6 pathway. This provides a strong rationale for the combined targeting of both the CDK4/6 and PI3K pathways in effective control of the tumor progression . Studies have suggested that inhibition of the either the CDK4/6 or the PI3K/AKT pathway, delays the onset of endocrine resistance . Combinatorial inhibition of both the PI3K and CDK4/6 pathways overcomes the resistance due to single agent inhibition by CDK4/6 by downregulating cyclin D1 and arresting cell cycle progression . Several combination therapy trials are underway to identify the best strategy to overcome endocrine resistance in ER+ BC. Trials that combine the CDK4/6 inhibitors with various PI3K/AKT/mTOR inhibitors are ongoing, with the aim to inhibit tumor growth and prevent relapse. The triplet inhibitor trial with ribociclib, fulvestrant and BKM 120 or BYL719 in HR+/HER2-negative advanced or MBC is one study aimed to study its efficacy and suitability as a mode of treatment in these patients.
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Estrogen Receptor And Progesterone Receptor Positive Breast Cancer
Breast tumors are tested to see if they are estrogen receptor and/or progesterone receptor positive or negative. Hormone receptor tests are both prognostic and predictive. In general, tumors that are ER+ and/or PR+ are slightly slower growing and have a slightly better prognosis than tumors that arent. Hormone receptors also provide information about treatment options. If your tumor is ER+ and/or PR+, then your cancer can be treated with a hormone therapy. For this reason, these tumors are also sometimes referred to as hormone sensitive.
Hormone therapies slow or stop cancers growth by changing the hormonal milieu. For early stage cancer, these treatments include tamoxifen and a class of drugs called aromatase inhibitors or AIs. Currently, three aromatase inhibitors are approved for use by the U.S. Food and Drug Administration : anastrozole , letrozole , and exemestane . Studies suggest that all three are equally effective. Women with metastatic breast cancer also have other hormone therapy options, including fulvesrant , megestrol acetate , and tormifene .
Stem Cell Population And Transcription Factors
Cancerous/tumorous stem cells give rise to tumors/cancers and define their ability to proliferate and metastasize. They encompass the ability to regenerate or self-renew and initiate cancer progression, proliferation, migration and metastasis. The stemness of these cells are correlated with poor prognosis and endocrine resistance. A few of the biomarkers that define these subpopulations are CD44, CD24, CD133, and ALDH1 along with others .
There are possibly many transcription factors and associated pathways that may transform a normal stem cell to a cancerous stem cell, although two of the well-defined ones are: NOTCH and Hedgehog . The NF-kB pathway has been described elsewhere.
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Where Is Estrogen Made In Your Body
Endogenous estrogen production primarily occurs in your ovaries, but it can also be made by your fat cells. Estrogens are actually a group of hormones, not a single hormone:
- Estrone, produced mainly by fat cells and is the primary form after menopause.
- Estradiol, made in ovaries and is the primary form during your reproductive years.
- Estriol, the primary form during pregnancy.
The amounts and types of estrogen found in your body will vary during your menstrual cycle and throughout your life. These levels are influenced by external factors like your diet, medications, or endocrine disruptors .
All of these factors can contribute to hormone imbalances that show up with symptoms of estrogen dominance, and for some women, in turn, increase the risk of developing breast cancer.
Molecular Profiling: Implications For Future Clinical Trials In Er+ Breast Cancer
Although overexpression of any given oncogene or molecular target may identify the best group of ER+ patients to treat with a novel targeted therapeutic in a combination strategy to enhance endocrine responsiveness, it remains likely that only a proportion will gain benefit because of other co-existing mutations and molecular alterations within the complex web of inter-related signaling networks that will determine response and/or resistance to inhibition of any key target . As such, translational studies in samples from patients will remain crucial in optimizing clinical benefit from these new therapies, whether it is the original primary tumor or the relapsed sample in which the molecular profile may have changed.
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