Notch signaling pathway: architecture, disease, and therapeutics
Understanding ER-positive Breast Cancer
Having ER-positive breast cancer means a person's breast cancer cells have estrogen receptors (ERs). Receptors are proteins present in cells that can attach to substances in the blood.
Normal breast cells have receptors that attach to estrogen and progesterone, and these hormones help the cells grow.
Some breast cancer cells also have these receptors. Breast cancer cells with estrogen receptors are called ER-positive, and those with progesterone receptors are called PR-positive.
When these hormones attach to the receptors, they stimulate the cancer to grow.
If cancer cells have one or either of these receptors, doctors may refer to them as hormone receptor-positive, or hormone-positive, breast cancer.
This article examines breast cancer that is ER-positive. It looks at symptoms, diagnosis and treatment, outlook, and more.
When diagnosing breast cancer, doctors will take a biopsy of breast tissue. They will test this biopsy to see if the cells have estrogen or progesterone receptors, or both. If they do, doctors refer to it as hormone receptor-positive breast cancer.
Not having any hormone receptors means the breast cancer is hormone receptor-negative. Knowing the hormone receptor status is important in deciding treatment options.
According to the American Cancer Society (ACS), around two-thirds of breast cancer cases are hormone receptor-positive.
Hormone receptor-positive cancers — including those that are ER-positive — tend to grow more slowly than those that are hormone receptor-negative.
The treatment for hormone receptor-positive cancers involves taking hormone drugs that lower estrogen levels or block estrogen receptors. This can help prevent the cancer from growing and spreading.
People with hormone receptor-positive breast cancers usually have a better outlook in the short term. However, these cancers can sometimes return many years after treatment.
A number of factors may increase the risk of developing ER-positive breast cancer. These include:
The symptoms of ER-positive breast cancer are similar to those of many other types of breast cancer. The most common symptom is a lump in the breast.
Other symptoms of breast cancer can include:
A lump is a common symptom of breast cancer, but not all breast cancers cause lumps.
Learn more about other symptoms of breast cancer.
If a person notices a lump or other breast changes, or if these appear on routine screening, a doctor may suggest an ultrasound scan to gather more information.
If breast cancer is a possibility, the doctor usually recommends a biopsy to confirm:
During a biopsy, a medical professional removes a small amount of breast tissue or the entire tumor. They then send what they have removed to a laboratory for an analysis that includes immunohistochemistry testing.
The results of these tests help a doctor determine the best treatment plan.
Learn more about what happens during a breast biopsy.
Treatment for ER-positive breast cancer aims to reduce estrogen levels or stop estrogen from acting on ERs in the cancerous cells.
The choice of treatment depends on many factors, including:
The following hormone therapy options can help treat ER-positive breast cancer.
Luteinizing hormone-releasing hormone agonistsAnother name for this type of drug is "LHRH agonist." These medications can "turn off" the production of estrogen in the ovaries. As a result, less estrogen is available to support the growth of ER-positive breast cancer.
Examples of these drugs include:
This treatment is most common among females who have not entered menopause and have early stage ER-positive breast cancer. A doctor may combine this approach with another treatment, such as tamoxifen (Nolvadex, Soltamox).
Side effectsThese drugs can trigger temporary symptoms of menopause, such as:
Aromatase inhibitorsAromatase inhibitors block an enzyme called aromatase, which converts the hormone androgen into estrogen. Blocking aromatase reduces estrogen levels, so less estrogen is available to encourage the growth of ER-positive breast cancer cells.
Examples of aromatase inhibitors include:
These medications only work after menopause. They target the adrenal gland and fat tissue, where the body makes estrogen, but they do not prevent the ovaries from producing estrogen.
After menopause, females receive much less estrogen from their ovaries than they did before menopause.
Side effectsSide effects of aromatase inhibitors include muscle pain and joint pain or stiffness. In the long term, they may also increase the risk of osteoporosis.
Selective estrogen receptor response modulatorsSelective estrogen receptor response modulators (SERMs) attach to and block estrogen receptors in breast cells. This stops the estrogen from signaling to the cells to grow.
Examples of SERMs include:
A doctor may prescribe one of these drugs with another medication.
Side effectsPossible adverse effects of SERMs include:
Less commonly, SERMs may increase the risk of:
ER downregulatorsThese drugs also block the effects of estrogen. They change the shape of ERs so they do not work as well. They also reduce the number of ERs on breast cells.
One example of an ER downregulator (ERD) is fulvestrant (Faslodex). A doctor may prescribe it:
Possible adverse effects of ERDs include:
Prolonged use of ERDs can increase the risk of osteoporosis.
Preventive surgeryIf a person has not yet gone through menopause, a doctor may recommend surgery to remove the ovaries. This can reduce estrogen levels in the body and may help prevent breast cancer from returning.
However, this invasive approach can have a considerable impact. For example, it means that a person cannot conceive. A doctor should speak with the person about all the factors to consider.
Different organizations have slightly different recommendations for breast cancer screening. The ACS recommends yearly breast screenings for females ages 45 to 54 years.
It also states that females between the ages of 40 and 44 years should have the choice to start annual breast cancer screening with mammograms (X-rays of the breast) if they wish to do so.
However, each person's situation is different. A doctor may recommend a different screening schedule for someone with a higher risk of breast cancer.
A person can work out their risk of breast cancer using the Tyrer-Cuzick model, available online. According to the National Cancer Institute (NCI), a person with average risk of breast cancer does not need screening before the age of 40 years.
The outlook for people with ER-positive breast cancer tends to be good, especially when a doctor diagnoses it early.
A person with an early diagnosis of any type of breast cancer has a 99% chance of living for at least another 5 years, and often longer, the ACS reports.
However, if the cancer has spread to other organs, the chance of surviving for at least another 5 years is 29%, the organization notes.
Taking these steps may ultimately lead to a better outlook if a person develops breast cancer:
When someone has ER-positive breast cancer, the cancer cells have receptors for the hormone estrogen. This type of breast cancer typically responds favorably to treatments that block or destroy ERs or otherwise lower the body's estrogen levels.
The outlook tends to be good, especially for people who receive a diagnosis and appropriate treatment in the earlier stages of the disease.
It is important for people to regularly examine their breasts for any unusual changes and undergo regular screening when this is appropriate.
Breast Cancer Risk Management In Transgender Men After Chest Contouring Surgery
This study highlights the lack of clear guidelines for breast cancer management in transgender men after chest contouring surgery. While data is limited, the authors suggest adapting existing recommendations for cisgender women and implementing risk management strategies like pre-surgery evaluation and education.
Transgender men are in need of specific guidelines for breast cancer detection.Image Credit/ Rawpixel.Com - stock.Adobe.Com
A risk management approach is suggested for breast cancer detection in transgender men following chest contouring mastectomy, according to a study published in PLOS ONE. However, further education between patients and physicians is significant, while including patient decision making in the process.1
Chest contouring surgery, informally known as "top" surgery, is a plastic surgery procedure that shapes the skin and tissue of the chest to represent the contour of a male chest.2 This gender-affirming procedure allows transgender men to align their physical bodies to their gender identity, reducing cases of gender dysphoria.3
Gender dysphoria, as defined by the American Psychiatric Association, is psychological distress that causes incongruence between an individual's assigned sex at birth and their gender identity.4 Approximately three-quarters of transgender people experience gender dysphoria by the age of 7 years.5
According to the Global Cancer Observatory, breast cancer affects an estimated 47.8% of some 100,000 cisgender women.6 However, transgender male populations carry risk of breast cancer but current knowledge of the outcomes of procedures for both pre and post-operations are unknown.1
Evaluating Breast Cancer Risk in Trans MenThe systemic literature search began on March 14, 2023, and researchers applied the Swiss cheese model of risk analysis to illustrate how hazards can develop into an accident. For this study, the model displayed the hazard of breast cancer among transgender men, specific preventative factors, and any identifiable weaknesses in the prevention methods.
Cases of Breast Cancer in Trans Men After exclusion criteria, a total of 22 articles were included in the review with 5 of retrospective observational design and 17 case reports. There were 28 unique cases of breast cancer present and 9 of them were found after chest contouring mastectomy, with an average of 8.5 years' time till diagnosis. All 28 cases included patients that received cross sex hormone therapy prior to diagnosis with an average of 6.7 years between treatment and diagnosis. The ages of patients with breast cancer were between 35 years to 59 years old, with averages in the 40's range. Epidemiology of Breast Cancer in Trans Men One study reported the population of transgender men in a Dutch cohort had a breast cancer incidence of 5.9 in 100,000 men. Additionally, another Dutch cohort had an incidence ratio of 0.2 for transgender men compared with cisgender women but 58.9 for transgender men to cisgender men. In addition, transgender Dutch men had an earlier age of diagnosis of breast cancer, with an average age of 47 years vs 61 years for cisgender women. This was reflected in all 28 cases included in the review. One study had the oldest cohort evaluated for breast cancer incidence with 1579 assigned female sex at birth and 25% of patients older than 65 years old. "Detection of breast cancer in trans men at a younger age than cis women could be a result of age bias related to the rising incidence of gender dysphoria accompanied by a lack of long-term follow-up in an adequate number of trans men," the authors conjectured. Breast Cancer Screening in Cisgender Women vs Transgender Men Based on recommendations from the World Health Organization, all women aged 50 years to 69 years old should undergo biannual mammograms. Although, Swedish guidelines caution cisgender women to receive routine mammograms beginning at 40 years old and repeating every 18 months to 24 months until they reach 74 years old. Patients who are classified as high risk, usually BRCA1/2 carriers, are offered MRI screening from age 25 to 55 years. Ultrasounds are suggested for patients who have at least a 20% increased risk with dense breast tissue and are less than 50 years old. Guidelines for breast cancer screening in transgender men prior to chest contouring mastectomy are similar to the current suggestions for cisgender women, the authors noted; however, there is a lack of consistency in the existing recommendations for screening transgender men after chest contouring mastectomy. Some health care professionals suggest discussions between patients and physicians about screenings while others have advised annual chest and axillary exams, as others suggest mammograms every 2 years between ages 50 to 69. Histopathologic Examination of Breast Tissue From Cisgender Women vs Transgender Men Similar to chest contouring mastectomy for transgender men, reduction mammoplasty is a common surgery cisgender women undergo to decrease the amount of breast tissue, oftentimes due to physical discomfort or for cosmetic purposes. It is common for physicians to complete a routine histopathologic examination of excised breast tissue after reduction mammoplasty, regardless of the age of the patient. However, patients under the age of 40 typically weigh the costs versus benefits of histopathologic exams prior to committing to a decision. There were several differing suggestions found in the literature about histopathology after reduction mammoplasty procedures. Some believed patients older than 35 years should have a gross examination of breast tissue by a pathologist, then a histopathologic examination of up to 7 breast sections or up to 6 sections for patients older than 50 years. Other recommendations for histopathologic exams included patients beginning at age 30 years and all patients that underwent reduction mammoplasty should receive an assessment. The review did not find evidence of any existing guidelines for histopathologic examinations following chest contouring mastectomy for transgender men. There were some proposals suggested, including all excised breast tissue should undergo pathologic examination and recommendations of examinations of 4 tissue blocks per mastectomy. However, data showed no studies that had a confirmed practice as a clinical necessity. Comparison and Applicability Cisgender women who underwent reduction mammoplasty and transgender men who received chest contouring mastectomy have similarities and differences between them. Both groups have similar levels of variance in family history of breast cancer, ultimately affecting preoperative breast radiological or genetic screening. Additionally, both procedures require a negative family history of breast cancer to undergo breast remodeling. Based on these comparisons, guidelines created for reduction mammoplasty could reflect histopathologic examinations after chest contouring mastectomy in transgender men. Some differences between reduction mammoplasty and chest contouring mastectomy include the administration of cross sex hormone treatment in many transgender male populations. There is no consensus as to whether cross sex hormone therapy can affect the risk of breast cancer development, making it possible for transgender men to not adhere to existing guidelines for breast cancer screening. It is also unclear if transgender men will follow "consistent self-examination of the breasts, given that an aversion toward female secondary sex characteristics is common in patients with [gender dysphoria]." Surgical Considerations Regarding Breast Cancer Risk While some physicians may assume chest contouring mastectomy procedures produce the same outcomes as prophylactic mastectomies, some studies have found not all patients that undergo chest contouring mastectomy remove all breast tissue, making it irrelevant in eliminating breast cancer. Although, some studies have found the reduction of breast tissue can be linked to a lower risk of breast cancer. Cross Sex Hormone Therapy Often, it is assumed transgender men have less risk of breast cancer following chest contouring mastectomy because of their small amount of breast tissue and low levels of estrogen. This hypothesis does not necessarily reign true because high levels of endogenous testosterone in cisgender women is a risk of breast cancer. For transgender men that are administered high doses of cross sex hormone therapy, testosterone serum levels are higher than those in cisgender men and women. For cisgender women with high levels of testosterone, studies have found higher aromatase activity involved in estrogen production that leads to possible oncogenic pathways but the increased serum levels and the impact they have on breast cancer risk is unknown for the transgender male population. Breast Cancer Screening Modalities for Transgender Men While there are no reports of screening modalities for breast cancer in transgender men, guidance on screening in cisgender men can be effectively utilized. Following chest contouring mastectomy, mammography could show equal effectiveness in transgender men. However, some data showed complexity of mammography interpretation after reduction mammoplasty, suggesting a secondary modality for screenings after reduction mammoplasty and chest contouring mastectomy. There are some histopathologic studies that found an increased ratio of fibrous stroma in transgender men after receiving cross sex hormone therapy, making it unclear how this affects breast tissue and screening performance before and after the procedure. Screening-Related Harm Over diagnosis was found to be a major contribution to screening-related harm, followed by damage from radiation treatment, incidence of false positives or negatives, potential morbidity or mortality, and the psychological impact of the diagnosis. Risk Management Due to limited research, risk management is crucial for breast cancer in transgender men. This includes pre-surgery risk assessment, considering mammograms for high-risk patients over 40 years, and physician/patient education regarding residual breast tissue and follow-up. Until transgender-specific guidelines exist, adapting those for cisgender women is recommended. Conclusions on Screening in Transgender Men The review included studies that were all considered low to very low quality and were unable to conclude any epidemiology of breast cancer in transgender men. There were limited cases on the scope of breast cancer in transgender men. Prior to study initiation, the study protocol was never published and could potentially introduce bias. Based on the review findings, it is suggested histopathologic exams follow chest contouring mastectomy in transgender men as a breast cancer screening prevention method but if this is not feasible, guidelines for cisgendered women should be followed. References 1. Edvin Wahlström, Audisio RA, Selvaggi G. Aspects to consider regarding breast cancer risk in trans men: A systematic review and risk management approach. PLOS ONE. 2024;19(3):e0299333-e0299333. Doi:10.1371/journal.Pone.0299333 2. Masculinizing chest reconstruction ("top surgery"). Trans Care UCSF. Accessed June 20, 2024. Https://transcare.Ucsf.Edu/masculinizing-chest-reconstruction-top-surgery 3. Top/chest contouring surgery. Cooper Health. Accessed June 20, 2024. Https://www.Cooperhealth.Org/services/top-chest-contouring-surgery#:~:text=The%20procedure%20allows%20transgender%20men 4. Turban J. What is gender dysphoria?. American Psychiatric Association.August 2022. Accessed June 20, 2024. Https://www.Psychiatry.Org/patients-families/gender-dysphoria/what-is-gender-dysphoria 5. Zaliznyak M, Bresee C, Garcia MM. Age at first experience of gender gysphoria among transgender adults seeking gender-affirming surgery. JAMA Netw Open. 2020;3(3):e201236. Doi:10.1001/jamanetworkopen.2020.1236 6. Lei S, Zheng R, Zhang S, et al. Global patterns of breast cancer incidence and mortality: A population-based cancer registry data analysis from 2000 to 2020. Cancer Commun (Lond). 2021;41(11):1183-1194. Doi:10.1002/cac2.12207For Some Women, Hormone Therapy Isn't An Option. Are Menopause Supplements Any Better?
Menopause symptoms like hot flashes, night sweats, brain fog, mood changes and sleep problems can be a significant disruption.
Some people are turning to supplements to manage those issues rather than using treatments approved by the Food and Drug Administration, such as hormone therapy. But, experts say, menopause supplements aren't necessarily helpful. And, in some cases, they can be dangerous.
The rising popularity of menopause supplements, experts say, highlights a lack of access to evidence-based options, rampant misinformation about hormone therapy and gaps in our knowledge about menopause — even among specialists.
Current menopause treatments"The primary treatment — and the first-line treatment — should be hormone (estrogen) therapy, especially for moderate-to-severe menopause symptoms," Dr. Anna Barbieri, assistant clinical professor in the department of obstetrics and gynecology at Mount Sinai School of Medicine, tells TODAY.Com
"There is just nothing as effective and nothing that has as wide-ranging effects and benefits as hormone therapy," Barbieri adds.
Effectively managing hot flashes, most often through hormone therapy, may have long-term health benefits, too, Dr. Lauren Streicher, medical director of the Northwestern Medicine Center for Sexual Medicine and Menopause, tells TODAY.Com.
Not only do hot flashes last seven years on average (and often longer for Black women), but we also know that "hot flashes are associated with cardiovascular disease, brain fog during perimenopause, potentially declines in cognitive function down the road and multiple other medical problems," Streicher says.
However, some people should steer clear of hormone therapy due to other health conditions. That includes a current or past hormone receptor-positive cancer (primarily breast and endometrial cancers), as well as a history of stroke, blood clots or cardiovascular disease, Barbieri explains.
If someone can't or prefers not to take hormone therapy, that's where non-hormonal options come in. Those include the off-label use of antidepressant medications and the recently-approved drug fezolinetant.
There are also all kinds of lifestyle and behavior techniques people may use to stay generally healthy, whether or not those techniques directly help with hot flashes, Dr. Monica Christmas, associate professor and director of the Center for Women's Integrated Health at The University of Chicago Medicine, tells TODAY.Com.
That might include avoiding certain triggers (such as alcohol), cognitive behavioral therapy, maintaining good diet and exercise habits and even hypnosis, she says.
What doctors don't want is for you to jump into taking supplements on your own.
"I cannot tell you how many times I have identified supplements people were using that where unnecessary, potentially harmful or interacting with other medications," Barbieri says. "Or people who were using 25 supplements where they could just use hormone therapy."
Should you take menopause supplements?There are a lot of reasons someone might want to try an over-the-counter supplement to manage menopause symptoms. Of course, there's a wealth of options available on the internet — many with little or no evidence that they actually work, and some with evidence that they can be harmful.
"Most of them just haven't been studied," Streicher says. "But some of them we know absolutely are not safe to use."
In its 2023 position statement on non-hormone therapies, the Menopause Society (formerly known as the North American Menopause Society) did not recommend any dietary supplement to manage menopause symptoms. For the majority of the supplements the group looked at, their conclusions were due to flawed studies, mixed results or an overall lack of evidence.
The experts TODAY.Com spoke to generally agree, but take a more nuanced position: There can be a place for supplements in managing menopause symptoms, they say. But their usefulness depends on your symptoms, what other treatments you're comfortable with and the specific supplements you're using.
For Streicher, it makes sense to talk about supplements when patients have only mild symptoms, or if they have more intense symptoms and already take a prescription medication but want to try something on top of that.
A typical example for Barbieri might be a patient with breast cancer and sleep issues who can't take hormone therapy. "If someone does not use medication for sleep, and lifestyle interventions don't work, then we may turn to something like magnesium and l-theanine or inositol," she says, which research shows are safe for patients with a history of breast cancer who cannot take hormone therapy.
Other people "feel that menopause is natural ... And they just want to use certain lifestyle interventions and only feel comfortable with supplements no matter what," Barbieri says. "That's OK, I just need to know that."
More than anything, experts say, the decision whether to take menopause supplements should be based on a knowledgeable provider having a genuine conversation with a patient about what really might work for them and their preferences. (edited)
"As providers, we do need to be able to give good information and understand that (supplements are) going to be a preference of some people," Christmas says. "And if it doesn't work, (we need to be) respectful that maybe shoving hormone therapy down their throat still might not be the answer."
Common ingredients in menopause supplementsThere are a ton of supplements on the market, many of which contain proprietary blends of ingredients.
Additionally, supplements are not regulated by the FDA in the same way that pharmaceutical drugs are. It's up to the supplement manufacturer and distributors to ensure the safety and correct labeling of their products, the FDA explains.
That's why, if you're going to use any supplements, the experts recommend looking for a label that indicates it has been third-party verified, which means you can be more confident that it actually contains the ingredients that it advertises. Specifically, Barbieri suggests looking for USP or GMP supplement certifications on a product.
And keep the placebo effect in mind, Christmas says. When you take something new, you might feel better initially. "But the placebo effect can't be sustained," Streicher says.
Here are a few common ingredients you may see in menopause supplements:
Vitamins and mineralsIf someone is deficient in vitamins and minerals during menopause, supplements may be a good idea, experts say.
For instance, low levels of vitamin D are correlated with poor bone health and depression, Barbieri explains. "Because these are factors that are important for all of my menopausal patients, I will actually check vitamin D and will replace that — no question," she says.
The same goes for vitamin B12 and ferritin (a form of iron) which women may not get enough of via food, particularly those following plant-based or vegetarian diets. "These are essential nutrients that are going to result in improved health and sense of well-being if someone is deficient in them," Barbieri says.
If you think you could benefit from a supplement to treat a deficiency, talk to your doctor about testing first.
Isoflavones, phytoestrogens and "plant-based hormones"Phytoestrogens are plant compounds that mimic estrogen when broken down in the body. Isoflavones are a type of phytoestrogen that comes from soybean products.
This is a major category of menopause supplements, but they are not safe for people avoiding hormone therapy due to their health histories, the experts say.
"If you have a history of an estrogen-derived cancer, like a breast cancer, you shouldn't be taking (phytoestrogen supplements) either," Christmas says. "Those are nuances that maybe people don't think about when they see a supplement in the health food store or local pharmacy," she adds.
For those interested in phytoestrogen supplements who have a low-risk health history, Streicher recommends looking into S-equol. "It's the only one that really has science (behind it)," she says, "because it's the active metabolite of soy, which is what's been shown to actually potentially help with hot flashes."
Just keep in mind that people's experiences with these kinds of supplements vary widely, Streicher says, because people metabolize them differently.
While phytoestrogen supplements are not recommended for people avoiding hormone therapy, those patients generally are OK to eat phytoestrogens occurring naturally in food, such as soy, Barbieri explains.
What about general "plant-based hormone" products? Creams are often marketed with such language, Barbieri says, adding that they may contain a version of progesterone made in a lab using a compound in yams, she says. That language is aimed at people who want to feel natural by using that, but "plants do not have human hormones," she stresses.
Black cohosh"Black cohosh is commonly reported to help with hot flashes and night sweats, although it hasn't been proven to do that," Christmas says, "and it actually can increase liver enzymes."
If you have an underlying liver condition, you should steer clear of black cohosh she says. Or, if you decide to take it, "you should be monitored frequently with serology to make sure your liver function isn't worsening," Christmas adds.
St. Johns wortOften advertised to help with hot flashes and depression, St. Johns wort can also interact with many other medications that can have an impact on someone's health, Christmas says.
Combinations of herbsSome products contain a huge blend of many types of botanical ingredients and may or may not actually list the ingredients, Streicher says. For instance, you don't know what you're getting with products labeled simply "Chinese herbs," she says.
Before you try menopause supplements...It's tempting to just buy the bottle, but the experts discouraged trying a new supplement without talking to your doctor.
First, set up a doctor's appointment just to talk about menopause. Resist the urge to simply tack a conversation about menopause onto the end of another appointment, Christmas says.
Making an appointment specifically for menopause symptoms "automatically sets a different tone," she explains, and "it's probably going to get you a little bit more time in front of that health care professional." Ideally, this should be an in-depth and individualized discussion to go through your specific symptoms, what you've already tried and your treatment preferences.
Unfortunately, many doctors — even OB-GYN specialists — don't receive much (if any) training in menopause, Streicher says.
So, if your doctor isn't well-versed in menopause treatments, find a specialist. All the experts recommend starting by using this tool from the Menopause Society to find a menopause expert near you.
If you're in a major city, you'll likely be able to find someone pretty easily, Streicher says. But if not, telehealth consultation services like Midi and Gennev may be your best option. (Streicher provides educational work for Midi.)
This story first appeared on TODAY.Com. More from Today:
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