TNBC Can Change Hormone Receptor Status If It Comes Back

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo.

Jamie DePolo: Hello, thanks for listening. Triple-negative breast cancer, as the name says, is negative for both estrogen and progesterone receptors, as well as HER2 receptors. So, it’s hormone receptor-negative.

People diagnosed with this type of breast cancer aren’t offered hormonal therapy, like tamoxifen or an aromatase inhibitor, after surgery to reduce the risk of recurrence, which is the cancer coming back, and they’re not offered these medicines because the cancer is hormone receptor-negative. It’s thought that they wouldn’t be effective. 

My guest is Dr. Lisa Newman, a surgical breast oncologist who serves as chief of the Section of Breast Surgery at New York Presbyterian Weill Cornell Medical Center and Weill Cornell Medicine. Dr. Newman and colleagues recently published a research letter in JAMA Surgery that found that among people diagnosed with early-stage triple-negative breast cancer, nearly 33% of the recurrences or second primary breast cancers were hormone receptor-positive, so the hormone receptor status had changed when the cancer came back or when there was a new cancer. The results raised this question: Should people with triple-negative disease be offered hormonal therapy to reduce the risk of recurrence?

She joins us to discuss the research.

Dr. Newman, welcome to the podcast.

Dr. Lisa Newman: Hi Jamie. Thank you so much for inviting me.

Jamie DePolo: So, to start, could you tell us a little bit about how the idea for this study came about? How did you think to look at this?

Dr. Lisa Newman: Well, it really actually came about kind of incidentally and you summarized our findings beautifully. Thank you so much for that.

Our research group does a lot of work looking at breast cancer disparities related to racial ethnic identity. And as you probably know, and as many in your audience I'm sure [are] aware, breast cancer death rates are 40% higher in African-American women compared to white American women. And this disparity is at least partly attributed to the two-fold higher incident rates of these biologically aggressive triple-negative breast cancers in Black women compared to white women.

So, in our disparities research, we have been doing a lot of work looking at ways to mitigate disparities by improving triple-negative breast cancer outcomes and improving outcome from triple-negative breast cancer is relevant for all women because the disease is indeed biologically more aggressive regardless of a women’s racial ethnic identity.

One of the triple-negative breast cancer studies that we were conducting was actually looking at the use of pre-operative MRI in women planning to undergo lumpectomy surgery for triple-negative breast cancer and looking at whether a pre-operative MRI improved the outcomes in terms of reducing local recurrence rates by better selecting patients for lumpectomy surgery. Now, that study did not show value of pre-operative MRI, but that’s a different research project.

In the context of doing that study, however, we were looking at the biomarker expression of the women with triple-negative breast cancer who did develop a local recurrence or who did develop a new primary breast cancer. And just on an observational basis, I was quite intrigued to see that many of these women had hormone receptor-positive breast cancers that were developing, not necessarily additional triple-negative breast cancers. So, we decided to then launch this larger-scale retrospective study, the one that we published in JAMA Surgery recently. 

Jamie DePolo: Interesting. So, is triple-negative breast cancer more likely to recur than other types, subtypes, of breast cancer? Do we know that?

Dr. Lisa Newman: Yes. Unfortunately, we do know that triple-negative breast cancer is biologically more aggressive at the level of higher local recurrence rates or recurrences in the breast itself after a lumpectomy or on the skin of the chest wall after a mastectomy, and it’s more likely to recur in distant organs. Distant metastatic spread is higher for triple-negative breast cancers compared to non-triple-negative breast cancers. 

And I do want to backpedal a little bit to discuss this on a deeper format.

As you correctly mentioned in the introduction, we characterize a breast cancer as being triple-negative because we see that it is negative for the three biomarkers: estrogen receptor, progesterone receptor, and HER2/neu. We characterize those biomarkers based upon the initial breast cancer biopsy sample, but it is just a sample. Breast cancers can have a lot of heterogeneity in them. But in the initial stains that we apply to a breast cancer biopsy, we look for those three proteins that are over-produced by many breast cancers, the estrogen receptor, progesterone receptor, and a growth factor protein called HER2/neu. The cancers that are negative for all of these, we characterize as being triple-negatives. 

We have very effective medical or what we call systemic therapies that actually target the breast tumor cells that over-produce these estrogen receptor and progesterone receptor markers, and we also have targeted therapies that focus on the growth factor HER2/neu cancers that are over-producing the HER2/neu marker. But for the cancers that aren’t manufacturing any of those markers, we don’t have any targeted treatments. So, that’s one reason why triple-negative breast cancers are biologically more aggressive. 

The other reason is that triple-negative breast cancers usually represent the intrinsic breast tumor subtype called the basal subtype. So, for these two reasons, inherent biologic aggressiveness and the lack of targeted therapies, the triple-negative breast cancers are more likely to regrow after breast-conserving surgery, after mastectomy surgery, on the chest wall, and in distant organs. 

Jamie DePolo: Okay. That makes sense.

Now, you brought up the testing. So, I'm going to ask you, I've been following the research and talking to some other researchers, you know we have some of the new targeted therapies, even though they are tied to trastuzumab or Herceptin, which then brings chemotherapy…as an analogy, I know this isn’t exactly accurate, but I call it a smart bomb because the Herceptin brings the chemotherapy to the cancer cell.

But what they’re finding is that these medicines are effective even in HER2-negative disease. And so, I guess, what I've been wondering is, are the tests as refined as they need to be? In other words, if testing is showing on the biopsy that we have triple-negative disease, is it possible that we need…I don’t know if intense is the right word, but testing that can look at a finer level of positive or negative? Or do we still need this testing? Because I'm wondering now if some of these medicines seem to work for everything. I don’t know. I'm not a researcher, but…

Dr. Lisa Newman: Well, you could’ve fooled me. You rephrased there some very powerful and focused research questions that are the target and the basis for a lot of really exciting ongoing research.

So, as we alluded to before, a breast biopsy sample showing the cancer is only giving you that, a sample of the tumor. We definitely appreciate that breast cancers have a lot of heterogeneity. They can have different patterns within the same tumor lump when that tumor lump is first diagnosed and then over time these cancers can generate additional mutations or genetic aberrations that allow the cancer to beat some of the treatments that we provide initially. 

So, it is entirely possible that the cancers that we think of as being hormone receptor-negative and triple-negative, somewhere in that tumor biology, perhaps there is some hormone receptor positivity or some HER2/neu activity. We know that the targeted treatments work for the patient for the tumors that are predominantly hormone receptor-positive and the anti-HER2 treatments work for the cancers that are predominantly HER2 overexpressing, but there may well be a window of using these targeted therapies for the cancers that seem to have low expression of these markers. 

What you described was actually the subject of a fascinating study that was presented at the American Society of Clinical Oncology meeting, the ASCO meeting, last year, looking at National Cancer Database specimens of tumors that had low expression of estrogen receptor, less than 10%. The investigators found from this National Cancer Database study that if those patients with low ER expression received endocrine therapy, they had a survival advantage.

Historically, we’ve always thought that the low hormone receptor expression in conjunction with being HER2/neu negative portended for the behavior of a triple-negative breast cancer. It is true that they tend to be more aggressive, but this National Cancer Database study suggested that there probably is a window of opportunity to consider giving endocrine therapy to those patients, even though the bulk of their tumor is hormone receptor-negative. That kind of goes along with our study findings. 

It may be that these triple-negative breast cancer patients, whose disease is predominantly triple negative when they are first diagnosed, possibly there is some low-level hormone expression somewhere in the tumor and perhaps we can manipulate that low-level hormone receptor expression by giving endocrine therapies. At least in our studies, showed that this treatment may prevent local recurrences from that cancer, which is going to be important for patients. The type of recurrence that we most worry about, of course, is distant metastatic spread, but even a local recurrence can be a devastating experience for a patient because it means starting all over with breast cancer treatment or reinstating breast cancer treatment. So, if we can use some medication to prevent those events from happening, we may be able to provide an important service to our breast cancer patients. 

Jamie DePolo: Let me ask you this, is there any value…I know you said, so do the biopsy, the tissue is tested, the hormone receptor status, the biomarker statuses are determined. Is there any value, or maybe this is already done, I don’t know, when the breast cancer surgery is done, mastectomy, lumpectomy, and in theory the whole tumor is removed, of testing that again? I mean, is that already done? I don’t know how that works. 

Lisa Newman: It’s done sometimes. The frequency of how often it’s done will depend on the institution and it will also depend on the patient’s history.

In patients that have received pre-operative medical treatments, like pre-operative chemotherapy — and the triple-negative breast cancers often do receive pre-operative chemotherapy — if there is residual cancer found in the surgically resected specimen, we usually will retest that tissue. So, there’s a window of opportunity there to find out if there is some remaining hormone receptor expression in the residual tumor. 

Perhaps we should be testing these tumor specimens more broadly and sampling different areas of the tumor for different degrees of testing. But all of these biomarker analyses do cost money and so there are the fiscal issues associated with being more robust in this testing. Many patients will have their tumor tissue retested for these markers if they are transferring care from one facility to another facility. Some patients will request retesting of their biomarkers. And in some cases, our pathology colleagues can actually look at the tumor specimen and make an educated assessment that the tumor is likely to have heterogeneity and so they, therefore, need to do those biomarkers on different components of the tumor tissue. 

Jamie DePolo: Okay. Okay. So, I know that your study was kind of small and it was only done at one institution, but I was fascinated by the results. And it sounds like the retrospective studies are maybe starting to look at this a little more deeply in other places. Were the results what you expected? Is this what you expected to see? I mean, to me, nearly 33% seems really high. I’m just wondering, were you surprised?

Dr. Lisa Newman: I absolutely was surprised. We’ve all known that cancer cells do have this heterogeneity, tumors have this heterogeneity in their pattern, but I wasn’t expecting that heterogeneity to play out in the way that we found related to local recurrences and/or development of new primary tumors in the breast. The conventional wisdom has always been that if a woman develops a second new breast cancer or if she develops regrowth of the original cancer in her breast or on the tissues of the chest wall after a mastectomy, that the new cancer on the chest wall would replicate or recapitulate the biomarker expression of the first tumor. 

And historically, we thought that there would be a difference of that biomarker pattern in only about 10% of cases. So, seeing it occur in nearly a third was definitely striking to me and I think that it does portend the need for further research to look at larger numbers of patients and to look at the category of women that have low hormone receptor expression. We looked at completely triple-negative tumors. It will be an even larger patient population if we include the women who have low hormone receptor expression who are also usually not assumed to be candidates for endocrine therapy, based upon our results and based upon the study that I mentioned from ASCO looking at the National Cancer Database. 

Jamie DePolo: Is retesting…if somebody has a recurrence or a second primary, is additional biomarker testing, hormone receptor status, HER2 receptor status, is that automatically done or is that done only…

Dr. Lisa Newman: Yes. 

Jamie DePolo: So it’s automatically done. Okay. Perfect.

Dr. Lisa Newman: It certainly should be repeated in any patient that has either regrowth of the original cancer, what we call a local recurrence, or if she gets a totally new breast cancer. It definitely should be retested. 

Jamie DePolo: Okay.

So, your study raises the question, hormonal therapy for people with triple-negative disease to reduce the risk of recurrence or a second primary? So, I have to ask about side effects, because hormonal therapy can have some really, really unpleasant and troubling side effects. I believe the last study I looked at…I mean, I know the numbers kind of range, but it was anywhere between like 20 and 50% of women didn’t complete the full course of hormonal therapy because of side effects like joint pain, hot flashes, all those lovely things that go along with it. 

So, I guess I'm wondering, like, how do we weigh the side effects against nearly 33%? Obviously, it’s not going to help everybody. Is there a way…probably not, but I have to ask the question. Is there a way to figure out who would most benefit or is it so much more beneficial that everyone should get it? How do we weigh these?

Dr. Lisa Newman: So, you’ve definitely done your homework, Jamie. You're right on all of those remarks that you’ve made. Endocrine therapy, whether it’s in the form of tamoxifen, a medication that we call a selective estrogen receptor modulator, or if it’s in the form of the aromatase inhibitors, AIs, which we can give to post-menopausal women. Tamoxifen can be used in pre-menopausal or post-menopausal women. All of these medications do have substantial potential side effects and that toxicity does account for the non-compliance with complete therapy as you mentioned. 

We see vasomotor symptoms, those hot flashes and night sweats, they can occur in women taking any of these endocrine therapies. Tamoxifen carries the additional baggage of higher risk for what we call venous thromboembolic phenomena, where women are at higher risk for getting blood clots in the legs or blood clots that travel to their lungs. Tamoxifen can cause problems with the uterus and some women have even developed uterine cancer from tamoxifen therapy. For most women with breast cancer, the benefits of preventing breast cancer, metastatic disease, will generally outweigh those side effects. But for a woman trying to live her day-to-day life, sometimes those side effects are formidable and will cause them to discontinue treatment sooner than we’d like for them to discontinue treatment.

The aromatase inhibitors in post-menopausal women don’t have quite as broad a spectrum of toxicities as tamoxifen, but they can cause those vasomotor symptoms, and the aromatase inhibitors can aggravate osteoporosis and really weaken bone health. So, all of these treatments do come at a price.  

Now, these treatments are great for preventing metastatic breast cancer in women that have hormone receptor-positive breast cancer, but we also use them in the pure prevention arena for women that are at high risk for developing breast cancer but who have not had a breast cancer diagnosis yet. These endocrine therapies, however, will only prevent the hormone receptor-positive breast cancers. 

Now, one of the things that we've learned in trying to improve the acceptability of these prevention applications of endocrine therapies is that we can actually lower their doses and it will lead to fewer side effects with the same prevention benefits. So, I think that this ability to decrease side effects also makes the use of these endocrine therapies potentially more attractive for women that have either triple-negative breast cancer or low hormone receptor-positive breast cancer in terms of using them to try to prevent additional breast tumor events. So, I think that these low-dose applications are quite promising, but for any woman it is a difficult discussion, and the woman will ultimately have to weigh the pros and the cons of these treatments based on what she’s willing to tolerate in terms of toxicity.

Jamie DePolo: Right. And I would add, at least my understanding is, among the aromatase inhibitors if somebody is on that, they’re post-menopausal or even I've heard about some pre-menopausal women taking them, but with ovarian shutdown. If there are troubling side effects, they may be able to switch to a different one because there are three aromatase inhibitors. So, I have had friends where they started on one, it wasn’t good, they switched to another, and it was much better.

Dr. Lisa Newman: You are so correct. As you mentioned, I'm a surgical breast oncologist so I'm not going to pretend to be an expert in the chemical nuances of these different treatments, but it has absolutely always fascinated me that in my own patient population even though the three aromatase inhibitors are fairly comparable in the way that they combat breast cancer, patients indeed may poorly tolerate one and then do totally fine with another. Or they may have a lot of toxicity from one agent, they can take a holiday from that medication for a month or two and then tolerate it better later on. 

So, there are definitely options for women in terms of how to make the treatments more acceptable. So, a really important message to everybody in your listening audience, Jamie, is that we want our patients to be very and brutally frank with us about the side effects that they are experiencing so that we can try to guide them in terms of ways to mitigate those side effects without the patient discontinuing the treatments that may be life-saving for them completely. 

Jamie DePolo: Right. Right. That’s always the message when I talk to people, I try to get across is: Don’t suffer in silence. Talk to your doctor because there are things that can be done. You know, it’s not a one and done thing here. There are options. 

Dr. Lisa Newman: Absolutely.

Jamie DePolo: So, where do we go from here with this research? Are you planning to do a larger study? Do you think this could be practice-changing? If there’s a person listening right now that’s been diagnosed with triple-negative disease that they’ve been told, you have a high risk of recurrence, whether because it was in the lymph nodes or it was a particularly large tumor, would that person ask their doctor for hormonal therapy because they’re very scared…I mean, I know everybody has to have a treatment plan that makes them comfortable and for some people that’s going to be more aggressive and in some people that’s going to be less. How does this fit into the big context picture?

Dr. Lisa Newman: Well, I definitely agree with you that larger scale studies are warranted to see how these numbers play out with more robust statistical power. And again, I would like to expand the study so that we also look at the women who are known to have low estrogen receptor expression. But for a patient today that has either a triple-negative breast cancer or a low hormone receptor expression breast cancer, I do think that these women should have conversations with their physicians about whether or not they should consider endocrine therapy, possibly at a lower dose, to try to mitigate the side effects of those treatments. And it will come down to making a balanced decision, but that balanced decision has to be made after a frank, well-informed discussion with the multidisciplinary treatment team. 

Jamie DePolo: Okay. And I'm wondering too, you know, you talked about low hormone receptor expression, would somebody who has low estrogen, very, very low progesterone, low HER2, they would still be classified as triple-negative? I know different institutions maybe have different cut-off points, too. So, I guess I'm wondering, if a person knew the level of the two hormone receptors could that help them make, you know, sort of inform the discussion with their doctor? They say, I know I'm low, but I'm not zero. 

Dr. Lisa Newman: Yeah.

Jamie DePolo: Am I making sense?

Dr. Lisa Newman: Yes. Absolutely. That is a fantastic point, Jamie. I think that it is very important for our breast cancer patients to do the deep dive into their own reports and to see exactly what the biopsy, biomarker panel has demonstrated. And that will be a way for the patient to advocate for herself and have an informed discussion with her physician about the possibility of taking these treatments. And yes, in general, as an oncology community, we do tend to look at the low hormone receptor expression cases that are also HER2/neu negative. We tend to group them along with the triple-negative breast cancers in terms of their biologic behavior and their risk for future metastatic disease, but in terms of whether or not we can prevent future breast cancers, perhaps we should be looking more carefully at whether we can prevent additional new breast cancers or local recurrences with use of these endocrine therapies, even though the expression was low. 

In terms of our staging systems, if you have a breast cancer that has more than 1% estrogen receptor expression or more than 1% progesterone receptor expression, technically that is ER- and/or PR-positive, but we do know that less than 10% tends to behave more like the hormone receptor-negative tumors. As we've been discussing, that low expression might be a window of opportunity to intervene differently from what we have been doing in the past, however. 

Jamie DePolo: Okay. Dr. Newman, thank you so much. This has been so fascinating. So interesting. I can't wait for the research to be done because I feel like this could help so many people. 

Dr. Lisa Newman: I agree. I think it’s definitely something to keep exploring and we look forward to making more advances every day and improving the outcomes of our patients. 

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