The ride of a lifetime

Roller coasters and surprises and science, oh my!

Six Flags 1993. My sister had earned tickets to Six Flags in Houston, otherwise known as Astroworld, through summer reading, and our parents had taken us to the amusement park. While I notoriously have a pretty poor memory, even before chemo brain, I have one very distinct memory from that trip. What I remember most vividly is the frustration I felt about the height rules for rides and also being jealous of my sister for her height. Those of you who know us are probably laughing at the idea of my being jealous of my sister’s height. While neither of us are particularly tall as adults, I am juuust slightly taller than her. But at the age of six or seven, my sister’s ten year old height was one that I very much envied. I wanted to ride all of the biggest rides and was simply too short to be allowed on them, unlike my sister. She, however, wanted nothing to do with the biggest rides, despite her height advantage. I think I even tried to convince her to get on some of them so I could live vicariously through her, but she wasn’t buying it.

Six Flags 2006. History really does have a way of repeating itself. My friend is looking at the roller coaster with a healthy amount of trepidation. It’s her first time coming to an amusement park and she’s not particularly fond of the idea of stepping onto a roller coaster. But a group of us have managed to convince her that it’s not a particularly scary roller coaster based on what we can see from a distance. As we stand in line and inch our way closer and closer to the ride, I start to realize that the roller coaster, which was only scary to her from a distance, was downright terrifying up close for the uninitiated. The designers of the ride had done an excellent job of disguising the surprises that awaited unsuspecting riders. Once you were close to the head of the line, you could really start to see the loops, hairpin turns, and more. But the designers also likely knew that you’d waited in the hours long line at that point and were unlikely to turn back (the sunk cost fallacy perfectly at play). And so we boarded the ride, my friend in tow. She bravely endured what turned out to be one of the biggest rides at the park, and I believe she actually came to enjoy it. Or at least, that’s what she told the group after the ride.

Cancer 2017/2018. In many ways, cancer is like one of those huge big, bad roller coasters. From a distance, it is without a doubt scary. Close up, it’s terrifying. Your stomach drops with each loop and your heart beats faster as you crest to the top of a hill. But the similarities end there. With a roller coaster, you can see what comes ahead and you know that there will be a reprieve on the other end. You will ultimately find your feet back on solid ground within a few minutes. Unfortunately, the same cannot be said of cancer. There is no path in front of you, no real way to predict if your car is headed into a hairpin turn, a loop, has reached the top of a hill, is about to fly backwards at top speed, or is about to drop off the edge because there is simply no more track left. The ride simply never ends. There also appears to be an unwritten rule that an unexpected turn must enter the picture just as you think you’ve gotten used to, if not comfortable with, the ride. For me, that surprise made its appearance on 8/6/2018. A surprise that changed my plans to make this post the announcement that my treatment had ended. Disclaimer: please don’t read that last sentence and get too worried; the cancer isn’t back!

The next loop

When receiving radiation, the protocol at MD Anderson requires that I be seen by a radiation oncologist after every five doses. In my case, that means I’m seen twice a week. My radiation oncologist who was responsible for developing my radiation plan is actually out during the month of August and I have therefore seen a rotation of different radiation oncologists at each of my “see visits”. While my radiation oncologist might be out this month, she does keep track of me, along with all of her other patients, remotely. As a result, she asked one of her colleagues to provide me with an update regarding my cancer during my see visit on 8/6/2018.

I know I’ve been hinting at this news for some time now and haven’t provided an update. In fact, you’re probably getting annoyed with me as I seem to keep on delaying the news. The reality though is that I had very incomplete information initially and needed more data before I could truly understand the implications enough in order to communicate it here. After meeting with my medical oncologist last week, I feel like I finally have something of a handle on this latest twist. So I’ll start with the news first but then bear with me as I provide more background on my understanding of the science behind everything.

The news was that retesting was done on some of my biopsy tissues and as a result of the retesting, it was determined that my cancer is actually ER+ 10% and PR+ 5% instead of being purely triple negative. In English, that means that my cancer is estrogen positive 10% and progesterone positive 5%.

Still confused? Read ahead!

So, is this good news or bad news? The honest answer is that it’s nearly impossible to put into one camp or the other. In order to make sense of why, you’ll really have to read through all of the information below. I’ve tried to simplify things as much as possible, but this is pretty complicated stuff. If you still have questions, please ask me!

What does being estrogen and progesterone positive even mean? If you recall, there are three receptors that breast cancer is typically tested for – estrogen, progesterone, and a protein called HER-2. Pathology uses a certain staining technique to determine how many receptors the cancer cells have. If receptors for either the hormones or HER-2 are present in or on the cancer cells, then the hormones or HER-2 attach to the cells and fuel the growth of the cancer. Receptor status for the hormones (estrogen and/or progesterone) can range from 0% - 100%. That means that the cancer cell can have no receptors all the way up to the cancer cell being completely covered with receptors. If you are 0%, or negative, for all three, then your status is triple negative. Previous guidelines considered those who were weakly hormone positive, basically 10% or lower, as still being negative for that receptor status. But that thinking has changed with time.

Why does the receptor status matter exactly? The receptor status helps guide treatment plans as those with either hormone positivity and/or HER-2 positivity have additional treatment options available to them, unlike those who are triple negative. The receptor status essentially helps doctors provide patients with additional tools to fight their cancer, primarily after they have finished their trimodal treatment.

So if you’re actually hormone positive but were initially identified as triple negative, did you receive the wrong treatment? In a word, no. With IBC, there is an existing standard of care for treatment for those in Stage III, which is the trimodal treatment I’ve referred to previously. That trimodal treatment encompasses chemotherapy, surgery and radiation. While I explained in my last blog post that the approach to radiation is not quite firm within the protocol, the same does NOT hold true for chemotherapy. The chemotherapy trial that I was a part of included all of the drugs that you normally receive in the existing standard of care plus additional drugs. If anything, being initially identified as triple negative may have helped ensure that I could be a part of the study, which may have contributed to my pathological complete response (pCR) to chemo.

If you had a complete response to chemo, why did they even bother retesting anything? And how in the world can you go from being triple negative on one test to ER+ 10% and PR+ 5% on another? These were some of the foremost questions on my own mind when I was initially told the news. In fact, let me add one of my own questions – if I had a complete response, what tissues did they use to run this retest? To get to the bottom of these questions, I need to highlight two key points. The first is that oncologists have known for years that several (perhaps all?) types of cancers are heterogeneous in nature, not homogeneous. What that means is that not every cancer cell in a tumor looks and behaves the same. A biopsy of one spot of cancer and another biopsy just .5 cm away can provide different results as to the makeup of an individual’s cancer. While there won’t be big swings (e.g., going from 0% estrogen positive to 85% estrogen positive), there can be differences. The problem is that while doctors have known that cancers can be heterogeneous, they weren’t sure what to do with that information and/or how it impacted outcomes.

The second point is that recent studies indicate that cancer, especially ones that are estrogen positive, can often have microscopic cancer cells that break away before the cancer is detected. These cancer cells appear to drift to other parts of the body, even perhaps the bone marrow, where they then become dormant. At some point in time in the future, these dormant cells can be triggered to become active again resulting in either a recurrence, a metastasis, or both. Because these cells are undetectable due to size (lack of mass) and are dormant, it is hypothesized that they are not impacted by chemo that is administered once the cancer is detected. The dormant cells can reactivate at any point in time – in one year or even twenty years down the road. Due to their dormant status, however, it is impossible at this point in time to find them or even study them to understand what reactivates them, whether they grow slowly or quickly once reactivated, etc. For those looking to learn more, this is just one paper that provides a bit of insight into this dormancy issue: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878717/.

My medical oncologist put these two pieces of information together (heterogeneous cancer and potential dormancy issue for estrogen positive cancer), and decided to play it safe by retesting my tissue. But since I had a complete response during chemo, the tissue from my mastectomy could not be used for this retest. Instead, MD Anderson needed to refer back to biopsy samples they had taken from me when I was first diagnosed.

These tissues were on hand for two reasons: 1) I had agreed to participate in an ongoing initiative at MD Anderson where they are trying to create a bank of tissue samples from women diagnosed with IBC. Right now, one of the biggest challenges to studying IBC, aside from lack of attention and funding, is that it’s such a rare cancer that it takes too long to collect enough tissues to study. This bank of samples will allow researchers to request samples to study and hopefully advance progress in the understanding of IBC more quickly. 2) Since I was participating in a chemo trial, the team needed to collect several biopsy samples at various points in time while I was receiving chemo in order to determine the effectiveness of the additional drugs I was being provided.

Using one of these samples, the pathology team retested the markers and determined that I did actually have some estrogen and progesterone positivity, albeit weak positivity for both.

You mentioned earlier that there might be additional treatment options available for those that are hormone positive. What are those treatment options? Let’s put progesterone positivity aside for a moment. In reality, all longer term treatments related to hormone positivity are currently focused on estrogen. Since I’m not HER-2 positive either, let’s also leave treatment options for HER-2 aside as that’s a whole different boat, and one that’s not applicable to me.

For those that are estrogen positive, endocrine therapy is often a long term treatment path that is pursued to try to control any remaining cancer and/or to reduce the chances of a recurrence or metastasis. In simpler terms, endocrine therapy is essentially hormone therapy and it is used to either add, block or remove certain hormones from the body. There are different types of endocrine therapies for estrogen positive breast cancer and the type used is usually driven based off of whether a woman is premenopausal or postmenopausal.

Premenopausal women are typically given a drug called tamoxifen which works to block estrogen receptors in cancer cells, thereby preventing estrogen from signaling growth to these cells. Women are asked to take tamoxifen daily for at least 5 years, although more recent studies have indicated a benefit of taking it daily for 10 years. Tamoxifen, however, is not an easy drug to take. While it has been on the market for many years, it comes with a host of side effects, which I’ll discuss later. Another alternative for premenopausal women is to combine ovary suppression with the use of an aromatase inhibitor. Aromatase inhibitors are typically reserved for postmenopausal women as they are not as effective as tamoxifen in premenopausal women. In order for a premenopausal woman to use an aromatase inhibitor, she must first suppress her ovaries, effectively entering menopause, either through monthly injections or through more permanent options such as removing her ovaries.

Since you are estrogen positive, does that mean you need to start endocrine therapy? If I haven’t lost you yet, then I might just lose you in this section. There is essentially no clear cut answer for me. While I am estrogen positive, I am only weakly so. Until recently, 10% or lower estrogen positivity was essentially viewed as being negative. Doctors and scientists are still struggling with how to treat women who are weakly estrogen positive. From the limited data available, it appears that cancer in this weak estrogen category tends to generally behave more like triple negative than it does more strongly positive estrogen cancer. But because of the dormancy issue and the fact that no one knows what triggers dormant cancer cells to become active again, there might be a benefit to using endocrine therapy for women who are even 1% estrogen positive. The data is simply unclear.

A retrospective study of over 9000 women with “regular” breast cancer was conducted to see if they could more clearly define the right threshold for ER positivity. In the study, they split their population into two categories. The first were those with weak estrogen positivity, which they defined as being 1-9%. The other category was comprised of women who had 10% or higher estrogen positive cancer. They then looked at the recurrence free, metastasis free, and overall survival rates between women in these two categories who either a) received endocrine therapy or b) did NOT receive endocrine therapy. If you look at the two charts in column C of Figure 2 in this study (https://www.ncbi.nlm.nih.gov/pubmed/24562447), what you’ll notice is that overall survival rates for the 20 year horizon remain roughly similar regardless of whether endocrine therapy was provided or not and whether they fall into the 1-9% category or the 10% and higher category. Where there does appear to be some difference is in the women in the higher estrogen positive category and how steep the curve is between those who do receive endocrine therapy versus those who don’t in the first 5-10 years. The same doesn’t hold true for those in the 1-9% category though. Also, please recall that the percentage of survival rates identified here are NOT RELEVANT for IBC. I am extrapolating data from “regular” breast cancer to IBC, which is probably not the wisest move. But I am limited by the data that is available and am trying to navigate some very grey territory here.

You could argue that since I fall into the 10% or higher category, I should start on endocrine therapy. But there is a negligible difference between the 1-9% estrogen positive category and my 10%. Additionally, endocrine therapy comes w­ith a whole host of real and potential side effects and isn’t a permanent solution (e.g., you cannot be on it for the rest of your life). These side effects can severely impact quality of life, which is something I very much value at this point in time. If I have arguably limited time left on this planet (even if we’re talking twenty years), I think it’s important to take into account the WAY in which I spend those years.

Even my own doctor isn’t 100% pushing tamoxifen. Because the data is lacking, the side effects can be strong, and I had a strong response to chemo, she is only suggesting that I try it, but will not push if I decide against tamoxifen. Additionally, if I try tamoxifen and the side effects are too severe to continue, she will not recommend any other approaches to endocrine therapy as they would require the even more aggressive step of suppressing my ovaries. The decision is therefore in my hands.

So what exactly are the side effects of endocrine therapy that you’re seemingly so afraid of? Each individual is obviously different and responds to drugs in their own way. I’ll focus on the wide range of side effects that I’ve heard for tamoxifen because that is the drug that is most pertinent to this conversation. The risks and side effects I’ve heard are below, but please note that this isn’t a comprehensive list:

- Increased risk of endometrial cancer, blood clots, stroke, and cataracts

- Bone and joint pain (people describe it like walking around with the flu every day)

- Impact on bone density

- Depression, anxiety (sometimes severe to the point of having suicidal thoughts)

- Mood swings, irritability (several people have described it as PMS on steroids, every single day)

- Significant weight gain

- Hot flashes, irregular periods and/or the complete cessation of periods

- Fatigue, exhaustion (requiring naps throughout the day and/or the inability to work a full-time job)

- Shortness of breath

- Dizziness

- Nausea

- Headaches

- Vision changes

- Nausea

- Hair thinning

- Constipation

Well, you have a decision to make. Which way are you leaning? In some ways, it feels like this decision should be and is straightforward. But as I mentioned, I’m genuinely concerned with quality of life. My hands and knees already hurt from all the treatment I’ve received. I wake up every morning with my hands so stiff that I cannot bend my fingers. I have to slowly bend them a little, relax, bend a little more, relax again, bend them further, relax, and so on until my fingers are “warmed up”. My knees also hurt, both when I wake up and again any time that I sit down for 30 minutes or longer. I probably look like an arthritic 80 year old when I’m first trying to walk after waking up or after sitting down.

Honestly, I’m more concerned about a world in which the side effects are bad but not so bad that the decision to stop taking tamoxifen is easy. What happens if I have depression but it’s not to the point of being suicidal? What happens if I have bone and joint pain and gain more weight because of tamoxifen creating an even greater demand on my body and worsening the bone and joint pain? What if the fatigue is so bad that I cannot find the energy to do anything more than wake up and drag myself to some sort of work (or if I can’t work)? Do I tough it out for 5 to 10 years or do I call it quits? I’m a pretty stubborn person as I’ve mentioned before. Will I have the wisdom to step out of my own way if the side effects are that bad or will I push myself, as usual, to try to ride it out?

In the end, I know that if I don’t try tamoxifen and the cancer returns and is strongly estrogen positive, I will always wonder. I will wonder if I could have prevented it, if tamoxifen would have helped, etc. From that perspective, I will at least give tamoxifen a try. I also have to own up to the fact that mentally, I need to adjust to the idea that I will be on treatment for the next 5 to 10 years. For so long I’ve had this milestone of getting to the end of radiation and being DONE. Acknowledging that this is no longer the case is proving more difficult than I expected and has made me more emotional than I’d like to own up to. For now, I need to speak to my medical oncologist about the next steps to start tamoxifen, but as always, I will keep you all posted.