Heather McArthur, MD

 Could this approach help us with the patient we just saw? Is there a role for short-term endocrine therapy to help us figure out the biology and need for chemotherapy in these gray zone cases? What about longer endocrine therapy? Where might we utilize that? I’d love to hear from Sunil. Can we do that? How reliable is a suppression of Ki67 of less than 10%? If we give longer duration endocrine therapy, it takes a long time for us to know if it’s working. Should we get an intermediate Ki67? Should the cutoff be less than 10%? In the ALTERNATE trial, complete cell cycle arrest is 2.7%, but I don’t know if you can read that amount out. I’d love to hear Sunil’s thoughts. But let me ask the clinicians first. Should we be doing this? Should we be getting some preoperative endocrine therapy? Heather, what do you think?

 I love this idea. It’s very much aligned with where the field is moving in general, which is looking at response and biomarkers to predict who needs more and which patients can have a more de-escalated or optimized approach. I love this idea in general. It’s worth noting that there were no patients who converted from low to high. If you had a low Ki67 at baseline, there would be a limited role to re-evaluating, and maybe those patients wouldn’t benefit from this type of strategy. Then it’s limited to those who have high scores at baseline. It’s provocative. I’m not sure I’m ready to use this strategy in the clinic tomorrow, especially given all the issues around Ki67 testing that we’ve talked about already.

You mentioned the ALTERNATE trial. That was anastrozole [Arimidex] vs fulvestrant [Faslodex] vs the combination in the neoadjuvant setting for 24 weeks, with less than 1% pCR [pathologic complete response] rate for all of those groups. I don’t know what the right hormone therapy is to apply in this setting, or what the optimal duration would be, so I wouldn’t be prepared to do this in the clinic off study. But I’d love to see more of these tailored study designs and would be happy to participate in those.

 Thanks. How about you, Massimo? Do you guys do this at all? Do you think we should be doing some of this?

 Most of the time, we use neoadjuvant endocrine therapy in all the patients when we want to reduce the tumors but we don’t want to use chemotherapy because of the toxicity. In general, this is the use in the clinic in practice in the United States. This patient didn’t have a large tumor. She had a small tumor. She’s relatively young. In the context of a study, 2 or 3 weeks would be appropriate. It would be difficult to make the patient wait longer in general clinical practice because these patients obviously want to pursue primary treatment as soon as possible.

Part of the issue is also the heterogeneity in the Ki67. You can do a biopsy. You need to be careful that you biopsy the same area of the tumor so that you can trust that if you have the second measurement less than 10%, you’re properly selecting patients who continue endocrine therapy. It may be highly variable. This is 1 of the major issues when you do biomarkers: the accuracy, the producibility, etc. The answer from the German study looks perfect. I don’t think I’m ready to do this in everyday practice. I’ll certainly welcome a study and participate. We can certainly do that with specific questions and maybe together with a Ki67 try to find another way to measure biological response to treatment.

 Thanks, Massimo. Sunil, what do you think about Ki67 in this setting?

 First, it’s the best possible marker that we have. All other cell cycle markers that we have looked at haven’t worked well in predicting response to endocrine therapy or CDK4/6 inhibitor. At last we have something, as flawed as it might be. But it’s a good marker that one needs to tame and use in a consistent manner. That’s my first comment. The second is now we’re in the COVID-19 era where a lot of patients may not be willing to come inside our hospital for surgery. I’ve seen people use short-term endocrine therapy to tide the process until they can come in and feel comfortable enough to get surgery and chemotherapy, as the case might be. That’s an area that one can definitely use these short-term therapies on.

Lastly, Ki67 is like any marker. As Heather mentioned, this German study and the POETIC study show that none of the laws went into high on excision, clearly documenting consistency in the analysis that was done between the biopsy and the excision. We may blow up as much as we want about the marker not being consistent or have concerns about it, but only after we do these kinds of analyses will we know what the problems are. At least in the German hands and the British hands, the markers appear fairly consistent in spite of all the concerns that we have raised.

 Thank you so much. We have an innovative surgeon where I work, and I’m OK with this. If I got the upfront biopsy and the patient hasn’t had any endocrine therapy, that’s a good sample for 21-gene or 70-gene signature. It’s unadulterated. I can get good information. If it comes back and I see the patient and I’m scratching my head and don’t know if this is the biology that’s going to benefit from chemotherapy, they’re going to go to surgery first, we’re going to get all the information, and we’re going to meet again and put our heads together. But so far, the biology is looking somewhat indolent.

My surgeon has started putting the patient on endocrine therapy for a few weeks before surgery, and then come back and we have that Ki67 on endocrine therapy. I’m happy to have it. It’s 1 more piece of information. As long as it doesn’t get in the way of getting a prognostic signature or interfere in any way with chemotherapy, which I doubt would be the case because usually it’s in the context of a more indolent type biology. And particularly for that premenopausal patient, where she may have 1 node that looks suspicious on ultrasound and she may be in that 1 to 3 node range where the biology looks very indolent, you don’t want to give her chemotherapy. It’s 1 more piece of information. We’re talking to Nadia Harbeck, MD, PhD [University of Munich]. They find this very useful over in Germany. It’s interesting. I don’t see a downside to doing it.

At any rate, thank you guys very much. We’ve hit on some good controversies here and helped us a little. These things can help our tumor boards all the time. Sunil, I want to thank you. This whole Ki67 discussion and the vagaries of it is a steep learning curve for a lot of us. It’s good to hear you think that it’s been around a while, and once there’s some consistently applied methodology, the utility will be there for us. Thank you all very much. It’s been a pleasure talking with everybody. I hope this has been very helpful to everybody for your practice.

Videos

Heather McArthur, MD; Massimo Cristofanilli, MD, FACP; Sunil Badve, MD, FRCPath; and Joyce O’Shaughnessy, MD, comment on the role of preoperative endocrine therapy in HR-positive high-risk breast cancer.

Case 3: Role of Preoperative Endocrine Therapy in HR+ High-Risk Breast Cancer

 I wanted to mention 1 other scenario because it may be 1 additional piece of information that we’re leaving on the table. There are new data from Germany. We’re struggling with this woman here, and they say there’s 1 more piece of information you can get. Let’s talk a little about the ADAPT trial. This is the exact same patient, with 1 node positive, strongly ER [estrogen receptor] and PR [progesterone receptor] positive, and Ki67 of 10%, but there are focal areas up to 20%. There’s 1 node positive, a T2 lesion. Those are her clear margins of resection.

Before she goes to surgery, if we get a chance to see her first—or maybe our surgeons can collaborate with this—if she’s got a Ki67 above 10%, should she have 2 or 3 weeks of endocrine therapy preoperatively, or potentially even longer? Who’s a good candidate for longer? If Ki67 suppresses, can it help us avoid chemotherapy? Or if we want to go longer, should we recheck Ki67 and make sure she’s suppressed before we keep going on endocrine therapy?

People, particularly in the UK [United Kingdom], have pioneered the POETIC trial. You get the diagnostic biopsy upfront, you get the Ki67, they get 2 weeks of endocrine therapy, and then they go to surgery. What they’ve shown in this POETIC trial is that the curves we’re looking at—time to recurrence—is 2 weeks of endocrine therapy and looking at baseline Ki67 and then Ki67 at surgery. If they’re low-low—they start low and stay low—they do great with endocrine therapy alone. If they’re high-high—they start high and they don’t suppress—they do very poorly. If they start high and are more than 10% suppressed to less than 10%, they do intermediate. It’s a signal of endocrine therapy sensitivity and how well people will do with endocrine therapy vs needing chemotherapy.

The ADAPT trial from the West German Study Group is innovative. If we look at the red box on the bottom right, we’re looking at a mixture of pre- and postmenopausal women with 0 to mainly 3 nodes positive N1, but they did have an N2 and N3 cohort. But here we’re looking at N0 and N1. Those with 0 to 3 nodes who had a recurrence score of 12 to 25—that’s an intermediate recurrence score. And they got 3 weeks of preoperative endocrine therapy. The premenopausal patients got tamoxifen. The postmenopausal patients got aromatase inhibitor. Then they went to surgery. If they suppressed their Ki67 to 10% or less—that was called suppression—they just got endocrine therapy.

The primary end point was to take these patients who were pN0-N1 but had a really low 21-gene recurrence score, 0 to 11—which is really good—who just got endocrine therapy, and compared those with the patients with N0 to N1 and a higher recurrence score of 12 to 25 who suppressed their Ki67 and just got endocrine therapy to see if they did equally well. The answer was yes. Even though those women had a higher recurrence score—some had node-positive disease—if they suppressed the Ki67 without chemotherapy, they had about a 92.6% 5-year IDFS [invasive disease-free survival]. Those are very good results.

Here we’re looking at distant disease-free survival. Look at the top red box. Those are the premenopausal patients. In both groups, it was a 97% chance of being disease-free at 5 years. This is with the low Ki67 with the suppression. They said that this makes a big difference. This can tell us we can avoid chemotherapy. At the bottom, we see that if patients had 3 nodes positive, they didn’t do as well in this 12 to 25 risk group. They did really well if they were 1 node positive. But with 2 nodes, they did OK. With 3 nodes, we’re not going to be comfortable leaving off the chemotherapy. In Germany, they do this routinely and say this really helps. We see the premenopausal population on the left. We see the endocrine therapy responders, the patients who suppressed their Ki67, the 12 to 25 recurrence score group. Without chemotherapy, look how well they did. And the red is the patients who got the chemotherapy because they didn’t suppress. They did really well.

Joyce O’Shaughnessy, MD, reviews the case of a 42-year-old woman with node-positive, HR-positive high-risk breast cancer and discusses clinical data from the POETIC and ADAPT clinical trials.

Case 3: POETIC and ADAPT Trials in HR+ High-Risk Breast Cancer

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?

 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.

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?

 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.

 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.

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?

 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.

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?

 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.

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?

 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.

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.

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.

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

There was an update on the SOFT and TEXT clinical trial data from the San Antonio [Breast Cancer Symposium] this past year, looking mainly at the question of tamoxifen plus ovarian function suppression [OFS] with the LHRH [luteinizing hormone-releasing hormone] agonist, or the aromatase inhibitor exemestane [Aromasin] plus ovarian function suppression.

There are important prognostic variables that were carefully looked at in the SOFT and TEXT data. It was centrally done, with clinical and pathologic biomarkers. On each of these curves, the worse the prognosis, the more the benefit from the LHRH agonist, and the more the benefit from the aromatase inhibitor compared with tamoxifen. Ki67 is on the bottom left, and we can see the prognostic power of Ki67 in these patients with a Ki67 of 26% and higher having the worst. The patient we just talked about was mainly 10%, which is mainly in the really good risk group, but then she had some subclones that were at 20%. She had a bit of a mixed prognosis based on these central data from SOFT and TEXT.

We just had these great 13-year median follow-up updates. It’s good to see the long-term follow-up in these patients. About 60% or 65% of patients in the SOFT and TEXT trials were node-positive. You can see in the red box down at the bottom of everybody getting OFS and looking at exemestane vs tamoxifen. In the SOFT trial, the reduction in distant recurrence at 12 years was 1.9%, while in TEXT, it was 2.4%. The vast majority of patients in the SOFT and the TEXT trials were 

-negative. There was a small cohort of patients who were 

In this analysis of overall survival, those patients were taken out of the analysis, so we’re looking here at the 

-negative population. Down at the bottom is the bottom line looking at 12-year overall survival. There’s a 3.3% absolute improvement in overall survival using exemestane instead of tamoxifen along with OFS in these patients. It’s clearly very effective therapy that we have for patients, and they only got 5 years of therapy. Another question is duration. What do we do about duration in these high-risk patients? They only got 5-year therapy, but we can see here what the curves look like. With distant recurrence-free survival, it doesn’t look like there’s a big drop-off. Maybe there’s some carryover effect, but not a big drop-off in distant recurrence-free survival.

Joyce O’Shaughnessy, MD, leads a discussion on SABCS 2021 updates from the SOFT and TEXT trials for premenopausal women with HR-positive breast cancer.

Case 2: SABCS 2021 Updates on SOFT and TEXT Trials for HR+ Breast Cancer

I’d like to go on to the second case and see what you’re doing from a practical standpoint with these patients who fall within the gray zone because we need another clinical trial done to have the answer. But we don’t have the clinical trial yet, so we still have to advise these patients.

She has HR [hormone receptor]–positive high-risk breast cancer. She’s 42 and premenopausal. She has a palpable mass in the upper outer quadrant of her right breast, clinically negative axilla, and biopsy shows grade 2 invasive ductal carcinoma. ER [estrogen receptor] is 100%, PR [progesterone receptor] is 80%, 

 is 0, and Ki67 is generally low, but it’s noted that there are focal areas of Ki67 up to 20%. There’s no lymphovascular invasion and she doesn’t have a germline mutation. She undergoes bilateral mastectomy, which shows a 2.5 cm grade 2 invasive ductal cancer with 1 of 3 positive axillary lymph nodes, a 5 mm metastasis with no extranodal extension, and clear margins. This is middle-of-the-road biology, but node-positive in a premenopausal patient.

From a practical standpoint, would you send her sample for either 21-gene recurrence score or 70-gene prognostic signature? Would you recommend adjuvant chemotherapy to her? Or might that depend on what a signature showed? What endocrine therapy would you recommend for her? I wanted to show some updated data from RxPONDER that Kevin Kalinsky, MD, MS, [Winship Cancer Institute of Emory University] showed at the 2021 San Antonio Breast Cancer Symposium.

We all recall that patients in RxPONDER were both pre- and postmenopausal with 1 to 3 positive nodes. They’d already had surgery and had a recurrence score of 25 or less. Then they were randomized to endocrine therapy alone vs chemotherapy followed by endocrine therapy. The primary end point was IDFS [invasive disease-free survival]. These are the updated analysis that Kevin Kalinsky convincingly showed at San Antonio. There was no benefit at all in the postmenopausal 1- to 3-node population, with a recurrence score of less than 26. There was no chemotherapy benefit for IDFS or distant relapse-free survival. We had seen it before, and we still see it. We see a 4.9% absolute improvement in IDFS in the premenopausal population and a 2.5% absolute improvement in distant relapse-free survival. This is true whether people have 1 node vs 2 or 3 nodes, or women who have 0 to 13 vs 14 to 25 on the higher end or the lower end. They still get the same benefit from chemotherapy.

There was also an intriguing landmark analysis looking at the 2-year IDFS by regular periods or not. We’re looking at IDFS in the patients on the left randomized to chemotherapy alone—these are the premenopausal women—and on the right, the women randomized to chemotherapy then endocrine therapy. There’s also the women who at 2 years didn’t have menstrual periods in the blue vs those in the red who had resumption of menstrual periods. We can see that in endocrine therapy alone, not having menstrual periods improved IDFS, and the same was true with chemotherapy. Eighty percent of the patients in the chemotherapy group didn’t have periods at 2 years and their outcomes were better. Not menstruating was beneficial to patients. We’ve seen that in other studies in the past.

It raises questions. Sixteen percent of patients—the premenopausal patients—in the RxPONDER trial had an LHRH [luteinizing hormone-releasing hormone] agonist. That’s because the trial was started and mostly enrolled before we had the SOFT and TEXT clinical trial data. By today’s standards, the endocrine therapy wouldn’t be considered optimal for these higher-risk premenopausal patients because most didn’t get an LHRH agonist, so the question is whether the chemotherapy took the place of an LHRH agonist. Many people and I believe NRG Oncology and other cooperative groups are possibly going to collaborate together and do this trial again in the premenopausal population, but this time, the endocrine therapy would include an LHRH agonist. It would be plus-minus chemotherapy, but everybody would get today’s optimal endocrine therapy. We don’t have those data.

Experts in breast cancer review the case of a 42-year-old woman with grade 2, node-positive invasive ductal carcinoma and discuss updated data from the RxPONDER trial on adjuvant chemotherapy benefit in premenopausal women.

Case 2: HR+ High-Risk Breast Cancer

 What’s your experience with toxicity management? Have you had any particular difficulties? Has anything you’ve found helped the patients stay on it? Heather, what do you think?

 In regard to toxicity, particularly with respect to the diarrhea, I expect that almost everybody is going to experience diarrhea, and my nursing team is hyperaware of this issue. Good communication and early recognition are critically important. I find that if I can get patients through the first couple of months of treatment comfortably, they do very well after that. It’s important to be very proactive in those first couple of months and introduce loperamide early on. I don’t do it routinely as prophylaxis, but I do it at the earliest sign of onset of diarrhea.

 Thanks. Massimo, how about you? Any other challenges or guidance about toxicity?

 Patient education with your ancillary team is very important, even a pharmacist being involved early on. I’ve seen motivated patients who would go through this initial phase starting very early on loperamide, maybe even making some changes in their diet and talking to the dietician, and some of these patients are well over a year and a half already in their treatment and aren’t changing the dose.

Some other patients coming out of neoadjuvant therapy, as we have discussed in other meetings, aren’t always motivated. They feel the first fatigue and the first diarrhea that comes and they want to drop, no matter how much you explain the data and the reduction of risk. Very few patients who I’ve treated decide to drop after 2 or 3 months simply because they didn’t want to deal with an additional toxicity, primarily diarrhea and fatigue. We’ll learn more about patient compliance and how to manage this adverse effect, but with the more mature data indicated and the benefit there for patients who complete their treatment, we may be able to go to this place even with patients who have less motivation who feel they have already done enough and don’t want to continue.

 We’ll see some dose reductions, too. Some patients need it. It was about 42% who needed a dose reduction, so we’ll see how their benefit plays out over time, along with toxicity, because there are different ways to get people through those 2 years. I know you use abemaciclib [Verzenio], and we’ve talked about the FDA [Food and Drug Administration] approval. Let’s go around and get a summary from everybody about the practicalities of how we incorporate this into our practice. I’ll start with Sunil.

 Ki67 is proving to be a very valid marker for selection of cell cycle-based therapies in addition to what we have known for a long time in terms of chemotherapy. The challenge is standardization of reagent kits and, most importantly, assessment by pathologists. There’s considerable variation even on the same slides, and there has been considerable work done within the last decade by the International Ki67 in Breast Cancer Working Group to minimize this. Following guidelines is clearly important.

 Adjuvant abemaciclib should be considered and discussed in conjunction with hormone therapy for our high-risk patients with hormone receptor–positive breast cancer using either the FDA or the ASCO [American Society of Clinical Oncology] or NCCN [National Comprehensive Cancer Network] guidelines. It has become a standard of care with an impressive reduction in invasive disease-free survival and distant relapse-free survival events early on in the course of disease.

 I definitely think that abemaciclib at this point is standard of care for this high-risk category of patients, and we’re learning more about how to deal with adverse effects and possible complications. Two years of treatment for patients who have managed the initial few months is relatively easy. As oncologists, we want to see that these data persist over time. Maybe it’s going to affect overall survival. Maybe it’s going to also reduce late recurrence, and it’s a carryover effect from the initial effect. There are many questions that we want to be addressed, but only time and longer follow-up and maybe more biomarker studies will be able to tell us. Obviously, it’s the standard of care, but how much does it change the natural history of the disease for these high-risk patients?

 Thank you. I’d just add that for me, the sooner I can start talking about this with patients, the better. Of course, when you first meet the patient, that’s the best time, but there are patients who are into their chemotherapy, even early into their endocrine therapy, and we’ve got to introduce it. The sooner they hear about it, the easier it probably is. Because like you said, it’s 1 more thing for them and 1 more hill to climb. It’s well worth it, of course, but expectations make a difference. Thank you so much for a great, super helpful discussion.

Heather McArthur, MD; Massimo Cristofanilli, MD, FACP; Sunil Badve, MD, FRCPath; and Joyce O’Shaughnessy, MD, share insight on applying data presented from the monarchE study and the use of adjuvant abemaciclib in clinical practice for high-risk, HR+ early breast cancer.

Heather McArthur, MD | Authors

Articles

Case 3: Role of Preoperative Endocrine Therapy in HR+ High-Risk Breast Cancer

Case 3: POETIC and ADAPT Trials in HR+ High-Risk Breast Cancer

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

Case 2: SABCS 2021 Updates on SOFT and TEXT Trials for HR+ Breast Cancer

Case 2: HR+ High-Risk Breast Cancer

Case 1: Clinical Implications From MonarchE in HR+ Early Breast Cancer