Selecting Chemotherapy for Patients With ER-Positive Early Breast Cancer

Systemic Treatments for ER-Positive Early Breast Cancer: Part 1

In this expert roundtable series, Cynthia Ma, MD, Washington University School of Medicine in St Louis, Missouri, leads a 4-part roundtable panel discussion on updates in selecting the optimal treatment for ER-positive early breast cancer with Neelima Vidula, MD, Massachusetts General Hospital, Boston, Massachusetts, and Seth Wander, MD, Massachusetts General Hospital.

In part 1 of this discussion, our experts explore the issue of chemotherapy, particularly differences in treatment for pre- and post-menopausal women, and the role of anthracycline.

Transcript:

Dr Cynthia Ma:
Welcome to Oncology Learning Network. My name is Cynthia Ma. I'm the Professor of Medicine in the Division of Oncology at Washington University School of Medicine in Saint Louis, Missouri. It's my pleasure to moderate today's discussion on the management of early-stage ER-positive HER2-negative breast cancer. I'm joined today by a distinguished panel of experts in the field. Doctor Wander, Dr Vidula, would each of you like to introduce yourself, and tell us a little bit about your background? We will start with Dr Wander.

Dr Seth Wander:
Great. A pleasure to be with everybody today. Thank you, Dr Ma. My name is Seth Wander. I'm one of the medical oncologists at Mass General Hospital, in Boston. I have a clinical and translational research interest in ER-positive breast cancer and thinking about genomic mechanisms of resistance to antiestrogens and targeted therapies.

Dr Cynthia Ma:
Very good. And Dr Vidula?

Dr Neelima Vidula:
Thank you so much for having me, Dr Ma. I am also a breast medical oncologist at Massachusetts General Hospital in Boston, and I'm an assistant professor of medicine at Harvard Medical School. I'm also a clinical investigator in breast cancer, with an interest in precision oncology, breast cancer-associated chest wall disease, and novel therapeutics. And thank you again for having me today.

Dr Cynthia Ma:
Wonderful. So welcome, everyone, and thank you for joining us today. We know that over the years, there has been significant improvement in the adjuvant systemic therapies for patients with early-stage ER-positive, HER2-negative breast cancer, and we now have several options with adjuvant systemic therapy. These include chemotherapy, CDK4/6 inhibitors, endocrine agents, as well as PARP inhibitors for BRCA-mutated patient populations. But it can also be challenging in the clinic to choose appropriate management for an individual patient. First, I'd like to start with, chemotherapy decision-making.

Dr Vidula, can you speak to your decision-making process when it comes to chemotherapy, for patients with early-stage ER-positive, HER2-negative breast cancer. And would your approach differ if they are premenopausal or postmenopausal?

Dr Neelima Vidula:
Thank you, Dr Ma. Patients with ER-positive early-stage breast cancer will benefit from hormone therapy, but we also know that some of these patients will benefit from the addition of chemotherapy as well. We’ve actually become very sophisticated in recent years at determining who needs chemotherapy and who can safely omit it. The Oncotype test is a 21-gene recurrence assay that can help aid in this, determination. Very often, for early-stage ER-positive breast cancer, patients will go to surgery first, to have that pathological assessment done and have the tumor sent for this Oncotype test. This test is validated both in the node-negative and node-positive setting, particularly for postmenopausal women.

The TAILORx study enrolled more than 10,000 women who are both pre- and post-menopausal, who had ER-positive, HER2-negative, node-negative breast cancer. Patients in the study who had a score between 11 and 25 were randomized to either receive chemotherapy with endocrine therapy or endocrine therapy alone. Across the board for the entire study, there was not a significant improvement with the addition of chemotherapy in terms of disease-free survival. The disease-free survival with chemotherapy and endocrine therapy was 84% compared to 83% with endocrine therapy alone.

For postmenopausal women who had an Oncotype score that was less than or equal to 25, chemotherapy did not improve outcomes. However, for a subset of premenopausal women who had scores between 16 and 25, there was a modest benefit from chemotherapy, but it's not clear at this time whether this was truly from a cytotoxic effect from the chemotherapy, or the induction of ovarian suppression by the chemotherapy itself. However, in this patient population of premenopausal women with node-negative, ER-positive early-stage breast cancer who end up with an Oncotype score between 16 and 25, it is important to consider chemotherapy and weigh the risks and the benefits. However, for premenopausal women who had a score less than 16, this study did demonstrate that it is safe to omit chemotherapy similar, to the postmenopausal population.

For patients who have node-positive tumors, the RxPONDER study also led to the validation of the Oncotype test for, postmenopausal women. And in this study, more than 5,000 women who had 1 to 3 positive nodes were randomized to treatment with chemotherapy and endocrine therapy or endocrine therapy alone. For postmenopausal women who had an Oncotype score less than 25, there was no benefit to adding chemotherapy. The disease-free survival in this population with the chemotherapy and endocrine therapy was 91%. And in the endocrine therapy alone arm, it was 91%. So, no difference. However, all premenopausal women did benefit from chemotherapy.

In this study, the disease-free survival with chemotherapy and endocrine therapy in premenopausal women who were in the study was 93.9% compared to 89% with endocrine therapy alone. Although, again, we don't know how much of this benefit is related to the cytotoxic effect of chemotherapy, or potentially an ovarian suppression effect of chemotherapy. In general, with premenopausal women who have lymph node-positive tumors, I think it is important to consider utilizing chemotherapy, at least have a discussion about it, since all patients in this study who are premenopausal did benefit from chemotherapy.

In general, I use the Oncotype score as well as other clinical characteristics such as the patient's age, the number of lymph nodes that are involved, their menopausal status and the grade of tumor, whether there's lymphovascular invasion or not, to help decide whether the benefits of chemotherapy would outweigh the risks. And in some situations, like patients who have 4 or more lymph nodes that are involved, we generally do give chemotherapy because the risk of recurrence is higher.

Dr Cynthia Ma:
Thank you for that very comprehensive discussion on this topic. So, Dr Wander, do you practice similarly? And which patient population would you not consider to do Oncotype?

Dr Seth Wander:
Yeah. I completely agree with Dr Vidula’s excellent summary, both in terms of use of Oncotype in node-negative patients as well as in patients with a limited amount of node-positive disease. I think, we've been getting better as a field at deploying the use of Oncotype in broader patient populations for early-stage ER-positive breast cancer. But to your question, there are still a number of patients where I would probably not deploy Oncotype. Of course, in HER2-positive or ER-negative disease, we're not going to utilize Oncotype.

But perhaps more importantly, for patients that have bulky, clinically overt, node-positive disease at the outset. They would not necessarily have met criteria for inclusion in the RxPONDER study that Dr Vidula was just mentioning. And for many of those patients, we would still typically favor considering upfront cytotoxic chemotherapy, based on the data that Dr Vedula was just mentioning, particularly even with limited node-positive disease, even with lower Oncotype premenopausal patients. It's still difficult to exclude benefits of cytotoxic chemotherapy.

I think there are still many debates amongst those of us in the field about how much of the benefit is related to ovarian suppression, as we just heard about, versus a unique effect of cytotoxic chemotherapy and eradicating occult micrometastatic disease. I think the guidelines based upon the RxPONDER study would still suggest considering cytotoxic chemotherapy for premenopausal patients even with a limited amount of node-positive disease, even in the presence of a lower Oncotype.

In my own practice, I'm not necessarily sending an Oncotype on a premenopausal patient with with lymph node-positive disease that's identified, for example, on a sentinel lymph node at the time of surgery. Though obviously you can discuss the data from our RxPONDER and some of the uncertainty related to the impact of ovarian suppression.

Dr Cynthia Ma:
Yes. I agree completely. There is, in premenopausal women, a trial in from NRG that's going to assess, the benefit of any adding chemotherapy in these lower oncotype but higher clinical risk populations. Hopefully, that would give us more answers in regards to this question.

Dr Wander, what is your favorite chemotherapy regimen in this setting for these patients?

Dr Seth Wander:
I think most of us, across the US are using either TC —docetaxel [Taxotere] and cyclophosphamide [Cytoxan], which is typically given every 3 weeks over 4 cycles; or ACT — doxorubicin [Adriamycin], cyclophosphamide, and paclitaxel [Taxol], typically given dose-dense every 2 weeks over 8 cycles with the AC first then the paclitaxel coming second.

I think the theme that we'll touch upon throughout our discussion today is one of de-escalation, avoiding unnecessary toxicity for patients with early-stage ER-positive breast cancer. If you look at the benefit of anthracyclines in this patient population, analysis from the ABC studies, which was a conglomerate of several clinical trials looking at the benefit of inclusion of anthracycline, suggest that these medications are particularly beneficial in patients that either have ER-negative disease, disease that lacks estrogen receptor expression or patients with more extensive nodal disease, multiple positive lymph nodes, more than 3 or 4 positive lymph nodes. For most of us, if you have a patient that has node-negative ER-positive disease with an elevated Oncotype per the TAILORx study that Dr Vidula was just telling us about, we would typically utilize docetaxel and cyclophosphamide in an effort to spare unnecessary toxicity from the anthracycline.

In that case, also, many patients will opt to use a cold cap with good success rates. Success rates there are lower if you're going to have to include the anthracycline. Much lower risk of cardiac toxicity, secondary malignancy, et cetera. I think for patients that have more extensive nodal disease, like the patients we were just talking about with clinically overt bulky nodal disease, preoperatively we're typically utilizing dose-dense ACT, and for patients that, at the time of surgery, discover that they have more extensive regional lymph node disease with more than 3 or 4 positive lymph nodes, we're starting to think more about using ACT in that situation.

And then I think the last case that may be a little bit debatable, and I'm interested to hear, what the 2 of you think about patients that are technically ER-positive, but perhaps the degree of ER expression is low. They may meet strict criteria for ER-positivity, but maybe it's 10%, 20%, PR-negative. Looking more like kind of a luminal B, more aggressive high-grade tumor. I think you could debate the merits of the anthracycline there as well, if the level of expression is low enough.

Dr Cynthia Ma:
Dr Vidula, would you like to comment on that?

Dr Neelima Vidula:
I agree with what Dr Wander has said. In general, we reserve the anthracycline-based chemotherapy for higher risk tumors and node-positive tumors because based on that AC study analysis, although there hasn't been a head-to-head comparison of ACT versus TC, that data does suggest that there's not a whole lot of benefit to adding the anthracycline in node-negative patients. And then it's also important to consider other factors, like in our elderly patients who may have comorbidities, often avoiding the anthracycline is helpful. These do have toxicities, and I think we have to be mindful of quality of life, particularly in the curative setting.

The other thought that I have at this point is I think we're going to be seeing some data at San Antonio from the KEYNOTE study, which may change some of our approaches to a higher risk early-stage, ER-positive disease where we might potentially consider adding immunotherapy into the mix here. But we'll have to see that data.

Dr Cynthia Ma:
Yeah. I agree with you completely.

Dr Seth Wander:
I was going to say for the KEYNOTE, it's interesting the theme in ER-positive breast cancer has been de-escalation: use Oncotype, use less chemotherapy. And in triple-negative disease, which we're not focusing on today, the pendulum has swung, based on KEYNOTE 522, in the opposite direction with use of more chemotherapy, more immune therapy. So, it will be interesting to see, on the heels of updated data for immunotherapy and ER-positive disease, whether we're shifting also more in that direction with more treatment, which is sort of the opposite of the trajectory over the last 5 to 10 years.

Dr Cynthia Ma:
Yes, I think that just speaks to the heterogeneity of the ER-positive breast cancer. The tumor biology will probably play a big role in how to select these patients. Hopefully, in the future, we would have good diagnostics to guide us.