Case 2: Recommendations for Approaching Treatment of HR+ Breast Cancer

A panel of breast cancer experts share recommendations for adjuvant chemotherapy and endocrine therapy for a patient with HR-positive breast cancer and discuss approaches to toxicity management to increase adherence to therapy.

Joyce O’ Shaughnessy, MD: From a practical standpoint, we all struggle with this in our practice. This is a premenopausal patient with 1 positive node and intermediate biology. Do we send the patient’s sample for 21-gene recurrence score or do you just give her adjuvant chemotherapy? Does it make any difference what their signature shows? What endocrine therapy would you recommend? Sunil, I’ll start with you. Do you think that the Ki67 helps here? For example, if we had a Ki67 of 50%, maybe we wouldn’t send the recurrence score. If it were less than 10%, we’re like, “Does she really need chemotherapy? Let me send it, even though the studies show that she benefits from chemotherapy.” Can we use the Ki67 to help us figure out who to send the recurrence score on?

Sunil Badve, MD, FRCPath: Absolutely. There are a lot of data starting a sample from grade. Even in the original paper, talking about where oncotype was first described, grade of invasive cancer was a very significant prognostic factor regardless of whether you include a recurrent score in the model. The hazard ratio for grade 3 was always higher than the recurrence score. But the problem is there’s concern about variability in the pathology rates and between interobserver and interlab variability, so grade has never been used.

The same concerns exist with Ki67. The advantage of having a companion diagnostic is basically that there will be standardization of methods and practices that laboratories use, and that would be a major advantage to get consistency across the board in terms of how Ki67 is analyzed. Once we have that, one should certainly be able to use a high Ki67 as a good surrogate marker regarding which patients could be required to have these molecular assays or in which patients we may be able to get away with not doing so. But we need to build the trust of oncologists before people can use that as a routine practice.

Joyce O’ Shaughnessy, MD: Thank you. What do you guys do every day in practice with these kinds of patients? I’ll start with Massimo. We know the data from RxPONDER, but does the RxPONDER data have to apply to everybody? How do you interpret this?

Massimo Cristofanilli, MD, FACP: I struggle with these types of situations because of the Ki67 just mentioned. With 10% predominant, there’s a bit of 20%, so you may want to try to get some objective data. You’re looking for a reason to not give chemotherapy. If you get the oncotype, what will the recurrent score be? If it’s a low recurrence score, you feel motivated not to even consider chemotherapy. If you want to use the other test, the 70-gene, you have high or low risk. The hope is that you may have a low risk or low recurrence score. I’d use it. I’d order 1 of the 2. Our group probably feels more over the oncotype, but we’ll see what the reports look like.

My feeling, based on the pathological and clinical assessments, is that this patient may not need chemotherapy. I believe Ki67 is useful in that sense. In terms of endocrine therapy, I will use the combination of ovarian suppression and exemestane [Aromasin] based on the data that you showed. She’s relatively young. Obviously, we need to monitor her bone health. We have a number of issues with quality of life, but the benefit is there, especially if she doesn’t receive chemotherapy. That will maximize the endocrine therapy and cover that gray area that we just talked about.

Joyce O’ Shaughnessy, MD: Thanks, Massimo. How about you, Heather?

Heather McArthur, MD: I feel tortured about this decision in this case because there’s potentially some discordance in the clinical-pathological risk. At the end of the day, I probably wouldn’t order the oncotype, swayed by her age of 42, the islands with the Ki67 of 20%, and the lymph node involvement, particularly in light of the exploratory analysis that was presented from RxPONDER that even premenopausal women with microscopic involvement of a solitary lymph node derive benefit from chemotherapy. I probably wouldn’t order the test.

I probably would give her chemotherapy. The genomics don’t dictate which chemotherapy prescription we’d recommend, so this probably isn’t someone who I’d recommend dose-dense ACT [doxorubicin (Adriamycin), cyclophosphamide, paclitaxel (Taxol)]. That seems like a big hammer for a medium-sized nail. This is someone who I might consider for TC [docetaxel (Taxotere), cyclophosphamide]. If this were an older patient, I might even consider dose-dense CMF [cyclophosphamide, methotrexate, fluorouracil], which I’ve used on a number of occasions. We can talk about the rationale for that on another occasion. I agree with Massimo about the hormone therapy prescription of aromatase inhibitor with ovarian suppression.

Joyce O’ Shaughnessy, MD: Thank you, guys. I want to get your feel on duration. I’d use zoledronic acid. Some people use that routinely in this situation, even if the bone density is good, and then post-mastectomy radiation. Are there any toxicity issues? Is there anything you’d want to say toxicity-wise about helping to increase adherence? Heather, do you want to start us on this one?

Heather McArthur, MD: I’m not administering zoledronic acid routinely. I use it in selected patients who I believe are at a very high risk of recurrence and who at a minimum have osteopenia. It’s something that I might revisit at a later date if there’s significant bone loss while on the prescribed therapy, but it’s not something that I’d consider upfront for this patient specifically. I’d currently recommend 5 years of therapy with ovarian suppression and aromatase inhibitor. That’s what the data supports at this time.

With respect to toxicity management, it’s supportive management for things like arthralgias and sometimes hot flashes. I found acupuncture to be very helpful for a lot of my patients who experience hot flashes. Sometimes I simply change the aromatase inhibitor backbone from 1 to another with success. For some reason, some patients will tolerate a nonsteroidal very poorly but a steroidal very well. Sometimes it takes a little creativity, but it’s very rare in my experience that patients aren’t able to continue on their hormone therapy at all.

Joyce O’ Shaughnessy, MD: Thanks so much. I was just thinking, “What about this patient?” Now I have to do this in my head every day with patients. “Wait a minute. Is she a monarchE candidate?” She didn’t have a T3 cancer. She didn’t have a grade 3 cancer and she didn’t have 4 more nodes. She had some areas that were 20%, but most of it was 10%. What do we do? We call up our pathologist and say, “We really have to have above 20%.” Sunil, when pathologists go back and see in this context of making a huge impact on patients’ therapy, because there are mixed signals when people say, “But there are some areas that are 20%,” what do we do with that?

Sunil Badve, MD, FRCPath: That’s where the companion diagnostic criteria come of value, which is in congruence with the International Ki67 in Breast Cancer Working Group. What’s recommended is a global analysis of hot spots and cold spots and everything in between and then providing a single value that represents the Ki67 level of the tumor rather than of a spot. That would decrease the amount of angst that people get when you have varying levels of Ki67 reported out, because it doesn’t help anybody to have these 2 or 3 values thrown out. The central message should be, “Where are we? What is your consolidated analysis of a given tumor?” We’re not looking at 10 cells and saying, “All these 10 cells are positive, therefore it’s 100%,” and then going next door and none of the cells are positive and then calling it 0. That doesn’t help anybody. A standardized global method is clearly of value in this situation.

Joyce O’ Shaughnessy, MD: Thank you. Massimo, in monarchE, 5% of people didn’t have chemotherapy. This is a case where you weren’t particularly leaning toward giving chemotherapy if her 21-gene [recurrence score] came back low. But let’s say that she did have above 20%, but on the low end. Would you consider abemaciclib [Verzenio] for her in addition to endocrine therapy without any chemotherapy?

Massimo Cristofanilli, MD, FACP: Yes. I was going to suggest that maybe this is a study that we need to run. How do we eliminate chemotherapy once we have a strong estrogen-positive tumor? In luminal disease, where an effective combination of endocrine therapy could be as effective as chemotherapy and certainly less toxic, this question needs to be addressed in a prospective study. It would be difficult for me to present that option, even though there was a small group of patients in this study who received chemotherapy. We need to discuss very carefully with the patient. But those are the data. Now that we have all these studies, we know how to use molecular testing for predictive and prognostic stratification. We need to improve on the therapies and make sure de-escalation is properly done and we substitute this biological therapy in a way that substitutes chemotherapy.

To go back, I don’t use it routinely, like Heather suggests, because it modifies your remodeling. At this point, it can be also damaging in the long term, but certainly can have an effect on recurrence. In some patients, it’s extremely helpful. As you know, the whole field of bisphosphonate is addressed in a different way in Europe or other countries where it’s routinely used. But we need to be very careful. In terms of toxicity, I agree that the different aromatase inhibitor may have a different profile. Some patients hate when you start them on anastrozole [Arimidex], and when we change to exemestane, they do better and tolerate it and can go to the treatment. These treatments aren’t without toxicity, but they’re certainly more manageable than chemotherapy.

Joyce O’ Shaughnessy, MD: Thank you, guys. I very much appreciate that. Thanks for your opinions. We have different approaches to this one. I’m very flummoxed by that. Up to 20% gets me worried, so I’d probably call the pathologist and ask them to have a look at that. If there’s a high-risk subclone, I’m like, “I probably have to do chemotherapy.” But I don’t use chemotherapy in all these patients. I order these signatures and try to corroborate my clinical impression of low risk and then I optimize endocrine therapy if I feel like somebody will be adherent. I flex as well based on the biology.

Transcript Edited for Clarity

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