Will 30% of Early Stage (1-IIIA) go on to metastasize??
Comments
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Kelly ,
The basic fact is that more BCs are being discovered earlier and that makes it difficult to know what the real stats are because a decade ago people were often diagnosed when the disease was more advanced. Take me for example with 'only' LCIS. Most LCIS even now is only picked up when you are investigated for something else. But I have LCIS and just LCIS and there will be many more like me picked up with BC stage zero due to enhanced surveillance.
When I was first diagnosed I got hung up on the stats - then I decided that as I couldn't change the stats it would be better to use my time and energy on trying to keep healthy. I'm finding that hard work enough!
If I'm reading your signature right I think you are due surgery soon. Good luck!
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This is interesting: Long-term breast cancer recurrence risk linked to original TN status
13-11-2017 | Hormone-receptor positive breast cancer | News
Long-term breast cancer recurrence risk linked to original TN status
medwireNews: The risk for breast cancer recurrence increases at a steady rate for at least 15 years after the end of planned endocrine therapy and is strongly associated with the original tumor diameter and nodal (TN) status, meta-analysis data show.
The findings are based on the results of 88 trials involving 62,923 women with early-stage estrogen receptor (ER)-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy.
Hongchao Pan (University of Oxford, UK) and co-investigators from the Early Breast Cancer Trialists' Collaborative Group say the results have "implications for long-term follow-up strategies and [highlight] the need for new approaches to reduce late recurrence."
"The risk could be somewhat reduced by extending the duration of endocrine therapy, with greater absolute benefits for those at highest risk for recurrence," they add.
The researchers report in The New England Journal of Medicine that patients with stage T1 disease and no nodal involvement (T1N0) had a 13% cumulative risk for distant recurrence at 20 years. This increased to 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9).
The corresponding risks among women initially diagnosed with stage T2 disease were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9.
Similar results were observed for the risk for death from breast cancer, but there was no association between TN status and the risk for contralateral breast cancer, the researchers remark.
The team also found that tumor grade and the presence of Ki-67 antibody (which were strongly correlated with each other) only moderately predicted long-term outcome, despite being important independent prognostic factors during the first 5 years.
Progesterone receptor and human epidermal growth factor receptor type 2 receptor status also predicted outcome during the first 5 years, but had no impact on long-term prognosis.
When Pan et al further divided the patients according to tumor grade, they found that, among patients with T1N0 breast cancer, the absolute risk for distant recurrence during years 5 to 20 was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease.
The corresponding risks for any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively.
The study authors conclude: "Recognition of the magnitude of the long-term risks of ER-positive disease can help women and their health care professionals decide whether to extend therapy beyond 5 years and whether to persist if adverse events occur."
By Laura Cowen
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Lisey posted a link to a BC.org feature about the same Pan study in this thread back in November 2017. The ensuing discussion starts here:
https://community.breastcancer.org/forum/105/topics/812929?page=58#post_5089667
The underlying NEJM publication is here (full-text behind a paywall):
Pan (2017), "20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years"
http://www.nejm.org/doi/full/10.1056/NEJMoa1701830
BarredOwl
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Kellyoc, the problem with looking at it that way is that you lump a group of very diverse diseases together so for any particular individual, the analysis is useless.
For example, think of a different disease: Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (TEN). A lot of people have never heard of it, but it's pretty easy to understand. Usually as a response to an drug, the top part of the skin detaches and people get huge blisters. When those unroof, it's like having a serious burn. If it involves less than 10% of the body surface area, it's called SJS; more than 30% it's called TEN, 10-30% is considered "overlap," but it's all the same disease, just different degrees of severity. The fatality rate for SJS is roughly 5%, TEN is at least 20%. SJS is much more common; this isn't the exact number, but for easy statistics let's say 9:1. Take 200 patients: 180 of whom have a 5% risk of dying = 9 total, 20 who have a 20% risk == 4 total. Add them all together, 13 of 200 expected to die, = 6.5%.
Do you see how the risk associated with the more common, less serious range of the disease statistically overwhelms the more serious type? The family of a person with TEN covering 70% of their body would be sadly misled if told the risk of death is 6.5%.
In an analogous way, lumping all breast cancer together (the "combined" thing) helps nobody. Breast cancer is too diverse a disease, especially if DCIS is included. Many women with early stage disease have a great prognosis and a tiny chance of recurrence, but someone like me has a >40% chance of recurrence (20 years for me would be age 64, time that I'm hoping to be part of the prime of my life).
To lump us all together minimizes how serious and life-threatening more advanced breast cancer actually is. In the worst case, it perpetuates a popular misconception that the disease is trivial.
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41% with T2N4–9 (risk of recurrence over 20 years), taken above from Molly50's post. That would be me. Thing is, 20 years from DX I will be 69. Still "young" but not exactly a kid. So far I am 6 years out, and I have lived well the last 6 years. I make a serious effort to live in such a way that I can die at any time without deep regrets. I intend to continue doing so for however long I get. In the end, it makes no sense to ruin your life by ruminating on the prospect of dying, whatever your odds are.
Furthermore, I deliberately went for the most aggressive treatment possible at the time of my DX. My thinking was that research rolls on, however slowly, and the longer I can stave off a recurrence, the better the chances that some new treatment shows up in the meanwhile.
Lastly, as discouraging as that 41% stat is, I still have better than a 50/50 chance
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Good News, Bad News on Breast Cancer Survival Rate
More women are surviving breast cancer, but more than 40,000 will still die from the disease this year. Living with it hasn't gotten much easier, either.
Early detection and better treatments helped prevent 322,000 breast cancer deaths between 1989 and 2015.
A new American Cancer Society (ACS) report shows that the breast cancer death rate decreased by 39 percent during those years.
It's encouraging news.
But breast cancer remains a significant health problem.
It's second only to lung cancer as the leading cause of cancer deaths among women in the United States.
The disease affects women and men of all ages.
About 81 percent of diagnoses occur in women aged 50 and up. About 89 percent of breast cancer deaths also occur in this age group.
The ACS estimates there'll be more than 252,000 new cases of invasive breast cancer in women this year.
And more than 40,000 will die of the disease.
Stubborn disparities
Dr. John A. P. Rimmer, a breast cancer surgeon in Florida, told Healthline that a number of factors working together for the past 30 years contributed to the improved survival rate.
Among them are better diagnostic tools and surgical techniques, as well as newer chemotherapy regimens and targeted therapies.
The ACS report notes that not all women have benefited from these improvements.
The overall incidence rate was 2 percent lower in non-Hispanic black women, compared to non-Hispanic white women.
But from 2011 through 2015, the death rate was 42 percent higher in black women. This is a small improvement from 2011, when it was 44 percent higher.
The lowest incidence and death rates are among Asian and Pacific Islander women.
The report indicates that biologic, social, and structural factors all contribute to these disparities.
These include stage at diagnosis, other health issues, and access and adherence to treatment.
Also, black women have a higher rate of triple-negative breast cancer, a particularly aggressive form of the disease.
Disparities vary from state to state. Access to healthcare is still a problem.
"Breast cancer is very complex socially and emotionally," said Rimmer.
In his practice, Rimmer has seen women who skipped screening or didn't initially seek medical care due to lack of health insurance.
Delayed diagnosis and treatment affects chances of survival.
Others refuse all or part of treatment due to cultural differences or misconceptions. And there are some who choose nonconventional treatments that simply don't work.
Rimmer said that people aren't always forthcoming about the reasons why they don't show up for treatment.
What it's like to live with breast cancer
At the start of 2016, there were more than 3.5 million breast cancer survivors in the United States.
"If we treat you and you're alive, it's a good thing. But there's nothing good about breast cancer," said Rimmer.
He added that survivors often experience long-term consequences of chemotherapy, surgery, and radiation treatments.
Laura Holmes Haddad, author of "This Is Cancer," is one of those survivors.
The California mother of two received a diagnosis of stage 4 inflammatory breast cancer in 2012.
She was 37 years old.
To say her life changed would be an understatement.
"When I look back, I think about how naïve I was. The things I thought would be the hardest, like being bald, were actually the easiest for me. But the things I thought I would breeze through, like having both breasts removed and having breast reconstruction, were the hardest," Haddad told Healthline.
"Physically, I faced pain and discomfort and physical changes I couldn't have imagined," she continued.
Haddad lists nerve pain, nausea, sensory issues, and being bedridden among the physical side effects of treatment.
Then there's the mental and emotional toll.
"I felt angry and bitter at first, and sad. And then I felt guilty and helpless. And I tried to feel hopeful and I tried to laugh when I could, because everything just gets so absurd that you just have to laugh to relieve the darkness. I felt lonely and isolated, and that was tough. And then I felt grief and then I finally hit acceptance. And that felt good," explained Haddad.
For her family, it was a month after month marathon of logistical and emotional challenges.
Her husband helped as much as he could. But he also had to continue working to keep up with health insurance and mounting cancer-related expenses.
To get through it all, they relied on help from their extended family, friends, and community.
A new normal
"I still have nerve pain in my chest and discomfort, so it is hard to ever completely forget what you have been through," said Haddad.
She still sees her oncologist every three months. She'll need to take estrogen blockers for the rest of her life.
"Because I am BRCA2-positive, I have a higher risk of developing melanoma, especially after the extensive radiation treatment I had," she added.
That means seeing a dermatologist every three months and avoiding the sun as much as possible.
"I also have to keep my weight at a healthy level to lessen the risk of recurrence. Finally, I have to watch for lymphedema in my left arm because I had 14 lymph nodes removed. I also received radiation on my left side, leaving a high risk for developing lymphedema. I see a physical therapist and do daily arm exercises for that," she continued.
Haddad's pet peeve is that people often think of breast reconstruction after mastectomy as a "boob job."
"I can't tell you how many times people told me that at least I'd have a new pair of boobs at the end of it. I tried to smile and joke about it, but in the end, my bilateral mastectomy was one of the hardest aspects of having breast cancer. I will never, ever forget the day the bandages around my chest were unwound in the surgeon's office, a few days after the surgery," she said.
"But after all those challenges, I can tell you one thing. I do not take one second for granted. I really do try and pay attention to every moment, every interaction, every bird I see, every conversation I have. There is no time to waste on nonsense. And I wouldn't trade that," Haddad said.
Research is key
"Cancer cells are nasty and sophisticated," said Rimmer. "The amount of knowledge we have is huge, but the cellular mechanism is hugely complex."
He emphasized that breast cancer isn't a single disease. Some types are more aggressive than others.
He believes research is one way to keep the death rate on the decline, especially when it comes to targeted therapies for the most aggressive types of breast cancer. He also said it's important to identify high-risk women, such as those with BRCA gene mutations.
"At the other end of the spectrum, just simple things like getting a mammogram or going to the doctor when you have a lump are beneficial. Prevention is better than a cure," Rimmer said.
Clinical trials are crucial to developing new treatments.
Haddad took part in a clinical trial for the drug veliparib. She credits it with shrinking her tumor enough for surgery.
There are challenges to participating in trials, even if your health insurance covers all or part of the treatment.
For Haddad, that meant weekly plane fares, hotel nights, and other travel-related expenses.
"No one really tells you about the logistics of navigating all that while on chemotherapy," she said.
But she believes that funding research and encouraging people with cancer to participate in clinical trials is important.
Many people don't realize that breast cancer can still be deadly, according to Haddad.
"I also don't think they realize — I certainly didn't — how important medical research is in developing treatment options and hopefully one day a cure for breast cancer," she said.
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Should All Women Be Tested for Breast, Ovarian Cancer Gene Mutations?
Researchers say testing women age 30 and over would reduce the number of breast and ovarian cancer cases.
Evidence is growing that all women age 30 and older should be tested for the inherited gene mutations that can cause breast and ovarian cancer, according to British researchers.
"We could prevent thousands more ovarian and breast cancers through a population testing strategy, compared to the current practice of testing only high-risk women," Dr. Ranjit Manchanda, a gynecological oncology specialist at Queen Mary University of London's Barts Cancer Institute, told Healthline.
Testing all women age 30 and older also would be cost effective, Manchanda and colleagues wrote in a paper that appeared this month in the Journal of the National Cancer Institute.
The researchers used a complicated mathematical model to arrive at their conclusions.
Several cancer experts called the study solid and thought provoking but questioned some of the underlying assumptions.
Current testing practices
The most well-known genes linked to breast and ovarian cancer are BRCA1 and BRCA2.
Together, mutations on these two genes account for 5 to 10 percent of all breast cancers and 15 percent of all ovarian cancers.
Currently, medical guidelines recommend restricting testing for BRCA mutations to women who have been diagnosed with breast or ovarian cancer, or who have family members with breast, ovarian, fallopian tube, or peritoneal cancer.
Women who inherit a mutation on either BRCA gene have approximately a 17 to 44 percent chance of developing ovarian cancer and a 69 to 72 percent chance of developing breast cancer over their lifetime.
These women can reduce their cancer risk with specialized drugs, enhanced screening, or prophylactic surgery to remove breasts or reproductive organs.
On the whole, women who do not carry BRCA gene mutations have a 2 percent risk for ovarian cancer and a 12 percent risk for breast cancer over their lifetime.
But the current practice of limiting testing to high-risk women misses many carriers of BRCA mutations, research has shown.
One reason is that more than half of women with BRCA mutations do not have a family history of breast cancer.
Expanding testing
Manchanda and colleagues came to two conclusions.
The first is that it would be cost effective and life saving to add four additional genes — RAD51C, RAD51D, BRIP1 and PALB2 — when testing high-risk women for mutations.
Dr. Yuri Fesko, medical director for oncology at Quest Diagnostics, a leading diagnostic laboratory, agreed.
"We are learning very quickly that there are some additional genes that provide significant risk of breast and ovarian cancer beyond the classic BRCA testing," Fesko told Healthline.
However, physicians order only BRCA testing for many patients, said Fesko, in part because of health insurance plan limits, which are based on current guidelines.
The researchers' second conclusion is that expanding this broader panel testing to all women age 30 and older, or almost 100 million women in the United States, would be cost effective and life saving.
This conclusion is more controversial.
If that were done, 237,610 additional cases of breast cancer, or about 2 percent of breast cancer cases in the United States, could be prevented over women's lifetimes. Another 65,221 or roughly 5 percent of ovarian cancer cases could be avoided, the study estimates.
But several experts questioned some of the researchers' assumptions.
First, the researchers assumed that 1 in 147 women in the general population carries a BRCA mutation.
"That is far higher than most studies assume," Elisa Long, PhD, assistant professor at the University of California Los Angeles (UCLA) Anderson School of Management, told Healthline.
Long co-authored a 2015 study that concluded general population testing for BRCA mutations was not cost effective.
"The estimates that I've seen for BRCA mutations [in the general population] are more like 1 in 400, 1 in 600 or 1 in 800," said Long. "It's like looking for a needle in a haystack."
The researchers also assumed that a gene test would cost $330 in the United States.
But there is a wide range in the costs of such tests.
Direct-to-consumer testing for BRCA mutations offered by Color Genomics, for example, costs only a few hundred dollars. But testing by major laboratories that physicians typically use, such as Quest, costs much more.
"The billed amount can run into the thousands of dollars," said Dr. Leif W. Ellisen, program director for breast medical oncology at Massachusetts General Hospital.
The researchers said that if the test cost equaled or exceeded $772, testing all women for mutations would no longer be cost effective.
Ambiguous gene mutations
Gene testing can turn up mutations that scientists cannot yet classify as harmful or benign, so-called variants of unknown significance.
That happens 1 to 2 percent of the time for each breast and ovarian cancer gene tested, said Ellisen. That would rise to as much as 12 percent if 6 genes were tested.
"It is well documented in the [research] literature that many patients who have variants of unknown significance in this day and age are getting inappropriate and unnecessary treatment," including surgery," said Ellisen.
And, if testing for breast and ovarian cancer gene mutations were offered to all women, ambiguous results could far exceed harmful mutation results, added Ellisen.
Manchanda agreed that ambiguous test results are a serious problem.
"We need to do further research on how to monitor and counsel for variants of unknown significance," Manchanda said.
The U.S. Preventive Services Task Force, an influential independent, government selected panel of experts, is in the early stages of updating its 2013 recommendation that BRCA testing be limited to high-risk women. The task force weighs harms and benefits but does not consider cost effectiveness.
"There is a lot of interest in what population would benefit most from this testing," Dr. Alex Krist, a task force member and an associate professor of family medicine and population health at Virginia Commonwealth University, told Healthline. "So, it is fair to say that this is an area that we will be looking closely at."
Many cancer experts, including Manchanda, doubt the task force will recommend expanding testing to all women without more research on the benefits and harms.
But it is possible that the task force might recommend testing in all Ashkenazi Jewish women, a group at particular risk for harmful BRCA mutations, said Ellisen.
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i manage my fear of recurrence with meditation and -- although it may sound counter-intuitive -- by making a conscious effort to think about death a little bit every day, to get acquainted with it, so to speak, so that it's not so scary. the stage IV threads are very inspiring to me in that respect.
death is truly a taboo subject in our culture and i feel a little bit more enlightened now.
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ps- this doesn't mean that i am fatalistic, of course. i do all the things, the eating well, the turmeric, the exercise and whatnot.
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heart disease is higher deaths than bc.
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Stephanie, same here. Coming to terms with death has helped me live.
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GATA-3 Expression as a Predictor of Hormone Response in Breast Cancer
Purvi Parikh, MD, Juan P. Palazzo, MDLewis J. Rose, MD Constantine Daskalakis, SCDRonald J. Weigel, MD, PhD (FACS)
Correspondence information about the author MD, PhD Ronald J. WeigelPlumX MetricsDOI: https://doi.org/10.1016/j.jamcollsurg.2004.12.025
Background
Expression of estrogen receptor-α (ERα) as determined by immunohistochemistry of tumor tissue is currently the most clinically useful test to predict hormone responsiveness of breast cancer. Thirty percent of ERα-positive breast cancers do not respond to hormonal therapy. GATA-3 is a transcription factor that is expressed in association with ERα and there is evidence that GATA factors influence response to estrogen. In this pilot study, we investigated whether GATA-3 expression is associated with hormone response in breast cancer.
Study design
Breast cancer tissue was stained for GATA-3 expression by immunohistochemistry in ERα-positive cancers from 28 patients, 14 of whom were defined as hormone unresponsive (cases) and 14 of whom were age-matched controls with hormone-responsive, ERα-positive cancers (controls).
Results
Comparing cases and controls, there were no differences in expression of ERα; progesterone receptor, ErbB2; or tumor grade. Using 20% nuclear staining to characterize tumors as GATA-3 positive or GATA-3 negative, 6 of 14 (43%) cancers in the hormone-unresponsive group and none of the controls were classified as GATA-3 negative (odds ratio, 8.2; 95% confidence interval, 1.2−∞; p = 0.031). Using different cut points to characterize GATA-3 positivity yielded very similar results, indicating a positive association between lack of GATA-3 expression and lack of response to hormonal therapy.
Conclusions
The study suggests that analyzing ERα-positive breast tumors for GATA-3 using immunohistochemistry might improve prediction of hormone responsiveness. The association between GATA-3 expression and hormone response suggests that GATA-3 may play a role in mechanisms controlling response to estrogen.
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Does anyone know if GATA-3 is part of thhe Breast Cancer Index? (BCI)?
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Researchers identify presence of ER gene fusion proteins in treatment-resistant breast cancer
February 7, 2018At Magee-Womens Research Institute (MWRI) and UPMC Hillman Cancer Center, a large team of clinical and laboratory researchers dedicated to understanding treatment resistance in the most common form of breast cancer have identified a new genetic change in the estrogen receptor (ER) that contributes to therapy resistance. ER-positive breast cancer, diagnosed in two-thirds of breast cancer patients, is fueled by the presence of estrogen in the body. Anti-estrogen therapy is usually successful in treating the disease initially, but ER-positive breast cancers will often recur because tumors develop a resistance to treatment.
Published in the Annals of Oncology, the research identifies the presence of ER gene (ESR1) fusion proteins in treatment-resistant breast cancer. This is the first time that recurrent ESR1 fusion proteins have been identified in human breast cancer, and understanding how they function could lead to improved treatments for the disease.
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"We first identified this change in a patient who had ER-positive breast cancer, received anti-estrogen therapy, had her breast cancer recur and eventually passed away from the disease," said senior author Adrian Lee, Ph.D., director of the Women's Cancer Research Center at MWRI and UPMC Hillman Cancer Center, and professor of Pharmacology & Chemical Biology at the University of Pittsburgh. "A member of our lab noticed the mutation while performing posthumous genetic analysis from tissue in our organ donation program, and over time we were able to identify many more cases of this mutation in patients with recurrent disease." This work was performed in collaboration with Foundation Medicine Inc., a genomic testing company that examined ESR1 fusions in close to 10,000 breast cancers sequenced with the FoundationOne CDx test.
According to Lee, ESR1 fusion proteins "outsmart" traditional treatment by splitting in half and eliminating the binding site that anti-estrogen therapy targets.
"Physicians will continue administering anti-estrogen therapy, not realizing this genetic mutation has occurred," said Lee. "Now that we understand the change, though, we can detect it with a blood test and help improve treatments for this form of the disease."
According to Lee, genetic analysis will soon be the dominant field of ER-positive breast cancer research, eventually leading to improved treatments and patient outcomes.
"Genomic sequencing is telling us so much about breast cancer. I believe the research we are doing in the laboratory will have a significant clinical impact in the near future, and the work we are doing will play a large part in improving patient care and survival," said Lee.
Source:http://www.upmc.com/media/NewsReleases/2018/Pages/lee-breast-cancer-treatment.aspx
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Marijen, Is that related to this? https://www.nature.com/articles/cr201815
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I'm hoping someone like BarredOwl will talk me off the walls after i read this article. It appears 2/3rds of us have this variation. ugh.
Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells
"The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer."
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The science nerd in me is intrigued. Hoping they find a simple way to test for this so they know who should start with an AI and skip Tamoxifen. Having failed on Tamoxifen rather quickly, I found this interesting.
I did not catch the 2/3 number in the article, but I did not red every word of it; I skimmed a few parts that were a bit over my head.
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I used this to get the 2/3rds... The antibody was used to examine the expression of ERα36 in 1 677 human breast cancer samples from five independent cohorts. In the first cohort (Cohort Chongqing) of 1 068 cases, 734 (68.7%) breast cancer specimens were ERα66+ and 493 (46.2%) were ERα36+ Among 734 ERα66+ samples, 329 (44.8%) co-expressed ERα36. ERα36 was also detected in 164 of 334 (49.1%) ERα66− tumor specimens
1677 total and 1068 of those were ER+ cases:46.2 were ER36+ from the study (493)..
among the 734 that were ER66+, 44.8% co expressed ER36+.(329)
among the ER-, there were half that expressed ER36+ as well: (164)..
so of the 1677 cases 964 were ER36+... = 57% or close to the 2/3rds I estimated. -
I would say it’s related Lisey. And it seems that Tamoxifen “activates” the ERa36? They better start testing for it. Yes, we need BarredOwl for this
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It does seem like higher expression is the biggest problem. Hopefully it'll eventually be like HER2; they can measure if it's over expressed, and have a drug to target it. Hoping it comes in our lifetimes!
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I have been on the fence about when to upgrade to the "big girl meds" (what my stupid ex-oncologist calls AIs). I guess I probably will sooner rather than later. Tamoxifen resistance has always been a concern, plus I have the genetic polymorphism that means I don't properly metabolize tam to begin with. Seems like it would be a sure path to metastasis if I happened to have all of these problems combined, and we can't know when we aren't tested.
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Solfeo, when I read what your oncologist says, 'big girl meds', what a frickin asshole! Is this a joke to him? Are the side effects and the real concerns you have something for him to give pet names to? Oh my god, your big girl foot should kick him in his big boy ass!
I tell myself I am 'lucky' that tamoxifen offers me some hope. Because as much as I didn't want to do chemo, scared to death, I also felt that it was at least some sort of hunting party to actively KILL the dirty cancer. But no. No chemo for me. Chemo won't do me a lick of good. Take your tamoxifen and don't give it a second thought.
Well I do give it a second thought. The more I read the more I realize that tamoxifen has some pretty big holes in its protective shield. Right off the start some of us will never metabolize it. Then those of us who do metabolize it initially may, over time, develop a resistance to it. Oh joy.
The more I read this the more vulnerable and exposed I feel. Some days it's a battle to not feel like a sitting duck with a target on my back. I cannot say for sure but I don't think the Oncotype test looks into these genes. Maybe this test that we all placed our hopes in, holding onto those scores like lifelines, is going to go up in flames as not adequately covering the bases?
This calls for alcohol. Lots and lots of alcohol.
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Hi:
Hartmaier et al (2018), described in Marijen's feature, and Wang et al (2018), linked by Lisey, are different studies from different groups, and relate to different potential mechanisms of resistance to endocrine therapy. The full-length articles are available for free at the links.
======> Such studies about potential mechanism(s) of drug resistance may provide possible explanations for observed treatment failures. Such treatment failures are already baked into the statistics we have regarding distant recurrence rates in those who receive(d) the drug. Thus, such studies do not undermine the results of clinical trials that have established the therapeutic efficacy (benefit) of Tamoxifen or AIs in reducing distant recurrence, or the observed distant recurrence rates in patients receiving such treatments.
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Hartmaier (2018), entitled "Recurrent hyperactive ESR1 fusion proteins in endocrine therapy resistant breast cancer" is about ESR1 fusion proteins.
"Fusion proteins" are encoded by "mutant fusion genes", resulting from "genetic rearrangements" that break DNA and re-seal the break incorrectly, fusing a segment from one gene to a segment of a different gene.
They looked for and found various gene rearrangements in tumor samples, in which part of the estrogen receptor gene (ESR1) was fused at the DNA level to part of a gene encoding something else (a "partner gene"). This created a "fusion gene" which is part estrogen receptor and part partner gene, and it encodes a sort of "hybrid" fusion protein.
Interestingly, the fusion junctions occurred in the same area of the ESR1 gene in various fusions, resulting in removal of the estrogen-binding domain of ESR1. The estrogen-binding domain of ESR1 also happens to contain the site of action of Tamoxifen.
You might think removal of this domain would inactivate the estrogen receptor (with no place for estrogen to bind and activate it). But some fusions were "hyperactive" (more active than normal), despite the missing estrogen-binding domain, and this "hyperactivity" was dependent upon the nature of the partner gene portion in the fusion. Thus, some ESR1 fusion proteins display "constitutive, ligand-independent activity" (always "on" even without estrogen).
The activity of this type of ESR1 fusion protein would be resistant to inhibition by Tamoxifen (nowhere to bind), as well as to Aromatase Inhibitors (always "on" even with effective inhibition of estrogen synthesis by an AI).
Two Key quotes:
-- "Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers . . ."
-- "Our data establish ESR1 fusion proteins as recurrent, albeit rare, events, enriched in metastatic ER-positive breast cancer and likely contribute to endocrine therapy resistance."
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Wang (2018), entitled "Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells," is rather long and complicated.
I haven't studied it in detail. However, it does not relate to ESR1 fusion proteins.
Per Wong, "The 66 kDa estrogen receptor alpha [protein] (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment."
So, what is "ERα36"?
ERα36 is 36 kDa and is a shortened "splice variant" of ERα66.
-- Per Thiebaut (2017), ERα36 mRNAs have been found in normal ovary, uterus, breast and testis tissues as well as endothelial and vascular smooth muscle cells, kidney, cartilage, bone, lung and heart . . "
-- Per Soltysik (2015), ERα36 was found in most cells of animals at various ages.
-- Per Yan (2017), "ERα36 is a naturally occurring, membrane-associated, isoform of estrogen receptor α. The expression of ERα36 is due to alternative splicing and different promoter usage."
-- Per Omarjee (2017), "Several ERα variants, derived from the alternative mRNA splicing of ESR1 gene, have been reported, [3] including ERα-36. [4] The transcription of ERα-36 is initiated by a previously unidentified promoter located in the first intron of the ESR1 gene."
It appears that ERα36 can be found in normal cells, although levels may be aberrantly increased in some breast cancers.
The Wang study adds to the slowly growing body of work on this splice variant, and observed "agonist" effect of Tamoxifen on ERα36. Much remains to be done.
These types of pre-clinical, mechanistic studies should not deter patients from proven therapies.
BarredOwl
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Thanks BarredOwl. There are issues here for men, too, since tamoxifen is the post-treatment gold standard for us guys who are 90% ER+/HR+ HER2-.
I have a male friend who started on Femara nd went metastatic four years later, so the dilemma of changing from tamoxifen to an AI is not necessarily a sure bet.That said, my friend has been going well on all the mets treatments for nearly four years now and his onc is holding back a few treatments should the current ones fail to work.
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"Thus, such studies do not undermine the results of clinical trials that have established the therapeutic efficacy (benefit) of Tamoxifen or AIs in reducing distant recurrence, or the observed distant recurrence rates in patients receiving such treatments."
Correct in terms of the groups studied as a whole. If they are on the right track what it will do is identify the INDIVIDUALS who are more likely to recur within the existing larger statistical groups, where any person could fall on either end of the spectrum or anywhere in between. That doesn't mean my Oncotype DX score that gives me 9% chance of recurrence is wrong, statistically speaking, but it could mean I'm personally more likely to fall into the 9%. Statistics would eventually evolve as a result of the new information but that takes a long time and a lot of research.
I was going to add that AIs come with their own risk of developing resistance but that has now been said. I want to know exactly when tamoxifen has run its course so I can switch to an AI just in time to get the most life out of it too. Me and my pipe dreams!
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Thanks BarredOwl, I was hoping you'd show up. The fact is Tamoxifen doesn't work for some women and men... I'm an ultra rapid processor, so the other side of Solfeo on that, but like her, I'd like to know if I have the ER36+ or if it's the normal ER66+. This will change my course of which hormonal I'll continue with. I don't think there's any way to test for this after the fact, or is it a simple blood test?
I will admit this study had me more upset than the one I just read saying that Asparagus leads to breast cancer. ugh. Everything leads to cancer. -
these investigations are a window into the future of genomics.....and how it will and already does influence screening, therapeutics and the mechanics of how cancer works.....
For those of you who are interested in these topics, but are intimidated by the studies and find them over your heads, try reading Eric Topol, M.D's The Creative Destruction of Medicine.
I wish to add, on a more sobering note, is that when The Genome Project announced back in 2000 that all of the genes were “identified"...there was great hope that disease would shortly be understood and eliminated. Back then, “junk DNA" was just that, junk! But, today, scientists appear more humbled. it seems the more they learn, the less they know and “junk DNA" has proven not to be junk after all. With all of that said, another provocative book, written by Columbia University Professor, Stuart Firestein, Ignorance, How it Drives Science, gives everyone hope. What Firestein discovered, is, when you put a group of scientists in a room and ask them what they are doing, they don't tell you what they know, they tell you what they are working on and hoping to learn and discover....
Studies like these show us the discovery process that will one day, which I hope will be soon, will lead to better screening, diagnostics, treatments and hopefully a cure...
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There is a genetic disease that runs in my husband's family. The gene was discovered in 1993 and that came with promises of a cure within 5-10 years. When we found out my husband and son were at risk in 1998, we were told the scientists were 5-10 years away from a cure. Twenty years later we are probably still 5-10 years away. They have learned a lot in 25 years about what doesn't work and why, but not nearly enough about what does.
We weren't aware of the existence of the disease until after our son was born, and we chose to forgo having more children so as to not knowingly pass it on to another person. A lot of people took that promise of a cure around the corner to heart and had more children, counting on God and the scientists to save them. Some of those kids are dead now.
I'm not drawing any parallels to breast cancer research (I have high hopes), just agreeing with VR that "the more they learn, the less they know." -
Hi Lisey:
Re: "I'd like to know if I have the ER36+ or if it's the normal ER66+."
This is a candidate biomarker. Additional clinical research is required to establish its clinical validity and utility as a prognostic marker and/or in the selection of particular endocrine therapies.
Also, it does not appear to be an "either or" situation. Both forms (ERα36 and ERα66) appear to be found in normal cells.
In primary breast tumors, they detected expression of ERα36 in primary breast cancer tissues either with or without ERα66 expression (ERα66+, ERα36+ tumors; and ERα66-, ERα36+ tumors).
In addition, the level of ERα36 may also be important.
BarredOwl
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barred owl have you read anything about how the broccoli family sprouts specifically and mushrooms might therapeutically work to prevent mestasis? I k n ow john Hopkins was interested. One tumor was er+ one(I take tamoxifen for) was not. I worry that of the one kind doesn't get me the other will.
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