CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 17, 2023
Expiration: March 16, 2024
Joyce O’Shaughnessy, MD:
Johnston and colleagues1,2 presented an important update on the monarchE trial, with simultaneous publication in Lancet Oncology. In this randomized, open-label phase III trial, 5637 patients with high-risk, node-positive, HR-positive/HER2-negative early breast cancer received adjuvant ET with or without 2 years of abemaciclib. At this second interim analysis for OS, we now have 4-year iDFS and distant relapse-free survival (DRFS) data. All patients have finished 2 years of adjuvant abemaciclib, and the presented results have been updated for the intention-to-treat population, which combined cohort 1 (≥4 positive nodes or 1-3 positive nodes plus histologic grade 3 and/or tumor ≥5 cm) and cohort 2 (1-3 positive nodes with Ki-67 ≥20%).
Joyce O’Shaughnessy, MD:
There was a 6.4% absolute improvement in the 4-year iDFS rate with abemaciclib; that is highly significant. What is interesting is that even though the patients have completed their adjuvant abemaciclib now, over time the curves are continuing to separate. The absolute difference in iDFS continues to get larger over time, and there was excitement that there appears to be a carryover effect even after stopping the adjuvant abemaciclib.
Joyce O’Shaughnessy, MD:
Benefit with abemaciclib was seen in DRFS as well, which is most closely aligned with OS. Here, too, the curves appear to be continuing to separate further over time.
Joyce O’Shaughnessy, MD:
The OS data are still quite immature, with a 42-month median follow-up, but even so, for the first time, we can see that fewer patients have died in the abemaciclib arm. Currently, there are 50% fewer patients with metastatic disease in the abemaciclib arm vs the ET-alone arm. That difference is beginning to translate into decreased deaths and it is anticipated this will continue over time, which is encouraging to see.
Joyce O’Shaughnessy, MD:
Another important part of this update is the continued reassurance that patients get the same proportional reduction in their risk of having an iDFS event—recurrence or death—regardless of whether Ki-67 was <20% or ≥20%. It has become very clear that Ki-67 level is prognostic but not predictive of benefit.
Joyce O’Shaughnessy, MD:
No new toxicity emerged in this update. Approximately 44% of patients did require a dose reduction, so it is important to bear in mind that nearly one half of patients will need a dose reduction to complete 2 years of abemaciclib.
Joyce O’Shaughnessy, MD:
There are 2 take-home messages from the monarchE update at San Antonio this year. One was that there was a real sense of excitement that the initial benefit seen with abemaciclib is maintained as women have completed the therapy, and the iDFS and DRFS curves are continuing to separate with time. This benefit is real and continuing, and is seen regardless of Ki-67 level. I believe this is a real new standard of care, and there is hope that the FDA will remove the requirement for high Ki-67 from the abemaciclib label. The American Society of Clinical Oncology and National Comprehensive Cancer Network (NCCN) guidelines have always supported the use of adjuvant abemaciclib in the intention-to-treat analysis of monarchE. It is clear that a patient does not have to have high Ki-67 to benefit from abemaciclib, and it would be useful to have that reflected in the FDA label.
Editor note: The FDA has removed the requirement for Ki-67 testing for the use of adjuvant abemaciclib combined with endocrine therapy in patients with HER2-negative, node-positive, early breast cancer at high-risk for recurrence.
Sara A. Hurvitz, MD:
I think these data are very important and I have been waiting for them. With palbociclib in the phase III PENELOPE-B trial, we saw that the iDFS curves came together some time after completing adjuvant palbociclib, so that there was no significant improvement in iDFS at a median follow-up of 42.8 months.3 I was sort of holding my breath to see these monarchE data, and I am really quite pleased to see this continued separation of the curves. I think we are seeing that this drug is improving patient outcomes, and I’m very much looking forward to the longer-term OS data as they continue to mature.
Sara A. Hurvitz, MD:
At SABCS 2022, preliminary data were presented from the TRIO-US B-12 TALENT phase II trial evaluating neoadjuvant T-DXd in patients with HR-positive/HER2-low early breast cancer.4 All tumors were assessed centrally and locally, and HER2-low status could be confirmed via either local or central assessment. The 58 patients included were randomized to receive T-DXd alone or T-DXd with anastrozole. Initially, patients received 6 cycles of therapy. The study was later amended to 8 cycles of therapy because of the fact that some patients were getting close to achieving a complete response (CR).
T-DXd has demonstrated benefits in HER2-low metastatic breast cancer. In the DESTINY-Breast04 study of T-DXd compared with chemotherapy, T-DXd significantly improved PFS and OS, and had an ORR benefit.5 Now the question is, can we begin to see benefits with T-DXd in the neoadjuvant setting, where our chance of achieving pathologic CR with standard multiagent chemotherapy may be lower in those found to have HER2-low disease?6,7 If we were able to replace chemotherapy with an antibody–drug conjugate that could have less toxicity, that would be a win for patients.
Secondary TRIO-US B-12 endpoints include ORR, safety, and tumor biomarker analysis to look at how the tumor changed from baseline toward the end of the first cycle of therapy and to the end of treatment at surgery.
Sara A. Hurvitz, MD:
The ORR was based on imaging at baseline and at the end of treatment. Some of the patients are still on treatment, but among those who have completed imaging, 68% of the patients treated with T-DXd alone had an objective response vs 58% in the combination arm.
Sara A. Hurvitz, MD:
Level of HER2 expression was evaluated by immunohistochemistry by central assessment at baseline and again at the time of surgery. Of interest, approximately one half of the patients had a change in their tumor HER2 expression level from baseline to the time of surgery after receiving treatment with T-DXd. Of those who had a change, almost all (88%) had a decrease in HER2 expression. These results are very interesting and stimulate a hypothesis that perhaps one of the mechanisms of resistance to this HER2-directed antibody–drug conjugate is through downregulation of HER2. However, the immunohistochemistry assay can be problematic, and I think further work needs to be done to validate these early findings.
Sara A. Hurvitz, MD:
Some of the patients have undergone surgery and have results available on residual cancer burden. One patient in the T-DXd–alone arm had a pathologic CR and 5 patients—2 in the T-DXd–alone arm and 3 in the combination arm—had a near pathologic CR. More than one quarter of patients (24% in the T-DXd–alone and 31% in the combination arm) in this very small trial are still awaiting surgery, so additional results are anticipated.
Sara A. Hurvitz, MD:
The safety analysis shows that nausea and fatigue were the most common adverse events (AEs) in both treatment arms. There was one case of grade 2 interstitial lung disease (ILD) that resolved after holding therapy, and there was no grade ≥3 ILD. One patient died from a myocardial infarction following severe gastrointestinal-related dehydration.
Sara A. Hurvitz, MD:
These preliminary data are not practice changing, but I do think they provide a rich source of forthcoming information in terms of biomarkers that may be indicative of response or resistance to T-DXd. I eagerly await the final surgical results from both arms. I am intrigued by the fact that adding ET to T-DXd does not appear to benefit patients and may even lead to some resistance, with the lower ORR observed in the combination arm. Although these data are interesting, it is hard to draw conclusions from such a small study. We need more information before it can be used in any practice-changing way.
Joyce O’Shaughnessy, MD:
I agree this is a very interesting study, but it will not change practice today. Because not all HR-positive/HER2-negative patients receive preoperative chemotherapy, from this study I look forward to learning how T-DXd affects clinical outcomes in the patients we typically think may benefit from chemotherapy—those with higher-grade disease, lower ER, and other usual factors that we use to select patients for chemotherapy in this setting. Are outcomes with T-DXd as good as, or perhaps even better than, chemotherapy with preoperative doxorubicin and cyclophosphamide (AC), or even preoperative doxorubicin, cyclophosphamide and a taxane (AC-T)? My initial assessment is that T-DXd looks impressive in this unselected patient population—that it might be just as good as AC or maybe even AC-T. It would be great to be able to move away from AC and, perhaps, substitute T-DXd. We definitely need more data, but these preliminary results are encouraging. With the biomarker data, it will be interesting to see whether patients who did not appear to get much benefit from T-DXd simply have lower-grade disease and so are not going to benefit as much from any treatment. It would be very helpful to have that kind of information.
Joyce O’Shaughnessy, MD:
The OPBC-04 trial is a multicenter retrospective cohort study of 1144 patients with T1-4 early breast cancer with biopsy-proven nodal metastases.8 This analysis assessed the use of targeted axillary dissection (TAD) and whether it affects the risk of axillary and locoregional recurrence over time. TAD involves clipping a suspicious node and taking a biopsy of it, and if it is positive, resecting it after preoperative chemotherapy. This practice is not standard, and it is not clear whether it should be added to sentinel lymph node biopsy (SLNB). There was a big debate on this topic at the conference because there is still very little data showing whether TAD affects long-term outcomes.
The OPBC-04 trial is the first to compare outcomes with SLNB vs TAD. It is important to keep in mind, however, that it is a retrospective evaluation of patients with a mix of different breast cancer subtypes who achieved a pathologic CR with neoadjuvant chemotherapy.
Joyce O’Shaughnessy, MD:
The baseline characteristics for the patient population with respect to previous therapy, type of resection, and lymph node biopsy were similar between the 2 groups.
Joyce O’Shaughnessy, MD:
As we would expect in this type of retrospective analysis, the patients underwent a variety of treatments. I want to point out that the median number of sentinel lymph nodes removed was 4 in the SLNB group and 3 in the TAD group, which is an important difference.
Joyce O’Shaughnessy, MD:
Looking at the percentage of patients who had any locoregional recurrence, there appears to be a trend toward a benefit with the TAD at 3 and 5 years. However, it is very important to note that the median length of follow-up in the TAD group was only 2.7 years compared with 4.2 years for the SLNB group. We would expect to see fewer events with shorter follow-up, so this is comparing apples and oranges—we cannot draw any conclusions from this. Longer follow-up is needed—probably a median of 5 years in both arms before we can gain any insights from this retrospective analysis.
Joyce O’Shaughnessy, MD:
The debate at SABCS 2022 focused on whether to clip, with the goal of avoiding a false-negative pathologic CR in the axilla. The discussion was that the false-negative rate will be lower than 10% if you get at least 2 negative sentinel lymph nodes removed, and adding TAD to SLNB will give a false-negative rate <10%, even if you do not have 2 negative sentinel lymph nodes. The data so far suggest that the false-negative rate goes down if you add TAD to SLNB in patients who are clinically and pathologically node positive at presentation, but that may be because 20% to 25% of the time the positive node that is clipped is not a sentinel lymph node.9 It is an important question, but to date, the data have not proven that adding TAD is beneficial in a case where you remove multiple sentinel lymph nodes and they are all negative.
There are multiple other trials underway (NCT04671511, NCT05141630, NCT05071911), and we await additional data. Right now, adding TAD is not a necessary standard of care, but it is important to resect several negative sentinel lymph nodes at the time of SLNB following preoperative chemotherapy.
Sara A. Hurvitz, MD:
I agree with your analysis. I am looking forward to the longer-term outlook for these data, but this is a really key question that we face in our clinical practice, where we are using increasingly more neoadjuvant therapy. Addressing how to best manage the axilla and identify the nodes and learning how outcomes are affected by the response in the nodes is very clinically relevant.
Sara A. Hurvitz, MD:
I have been anticipating the results of the POSITIVE study for some time because it addresses a very clinically relevant question: Can a younger patient who wants to pursue a pregnancy after her diagnosis of HR-positive breast cancer safely pause her course of adjuvant ET and go on to achieve a pregnancy? And does such a pause affect outcomes?
POSITIVE was an international, prospective, single-arm trial conducted in patients who were 42 years of age or younger and had already received 18-30 months of adjuvant ET for stage I-III breast cancer, who had no clinical evidence of recurrence, and who desired pregnancy.10 Previous (neo)adjuvant chemotherapy was allowed, with or without fertility preservation. Upon enrollment, the 516 patients in the study stopped their ET and had a 3-month washout period. They then had ≤2 years off therapy to attempt to conceive and deliver, with or without breastfeeding. After that period of ≤2 years, patients would resume their ET to complete their planned 5-10 years of therapy. Patients were followed for up to 10 years. The primary endpoint was breast cancer–free interval (BCFI) from the time of study enrollment to first invasive disease or distant recurrence. Secondary endpoints included pregnancy and offspring outcomes, breastfeeding, and distant recurrence–free interval (DRFI). As an external control, the investigators compared the outcomes of these patients with those from the SOFT and TEXT trials.
Sara A. Hurvitz, MD:
The median age of the enrolled patients was 37 years, and approximately one third of the patients were younger than 35 years. Only 23% were age 40-42 years. The majority of patients (75%) had never had a previous birth. Of great interest, the majority of patients (93%) had stage I or II disease, so not many locally advanced stage III cases were seen here.
For ET, most patients received a selective estrogen receptor modulator, either alone or in combination with ovarian suppression. Only 16% used an AI with ovarian suppression. Almost two thirds (62%) had previously received chemotherapy.
Sara A. Hurvitz, MD:
With a median follow-up of 41 months, the cumulative incidence of BCFI events and DRFI events was 8.9% and 4.5%, respectively.
Sara A. Hurvitz, MD:
The investigators compared these values against the outcomes in the SOFT and TEXT studies of 1499 patients who did not have ET interruption. The outcomes from the POSITIVE study compare favorably with the outcomes in the SOFT and TEXT trials. Recall, however, that the majority of patients in the POSITIVE cohort were younger patients with stage I or II disease, whereas the SOFT and TEXT patients may have had slightly higher-risk features.11
Sara A. Hurvitz, MD:
Looking at outcomes based on subgroups, it is not surprising that patients who had positive nodes or larger tumors tended to have higher rates of breast cancer recurrences—either invasive or distant. There seems to be a trend toward a higher risk of recurrence with a higher tumor grade. Patients with features that may be surrogate markers for worse disease characteristics, such as having a mastectomy or anthracycline-based chemotherapy, also tend to have higher rates of disease recurrence.
Sara A. Hurvitz, MD:
One interesting aspect of this study was an 18-month landmark analysis based on whether a patient had a pregnancy by 18 months. Those who had not become pregnant by 18 months appear to have a bit higher cumulative incidence of BCFI events than those who did have a pregnancy by 18 months. Comparing the hazard ratios of univariable and multivariable analyses, it is very interesting to see that those who achieve pregnancy do not have worse cancer outcomes. These data really support what we have seen in multiple other observational trials: Pregnancy does not appear to be harmful to patients following a breast cancer diagnosis.
Sara A. Hurvitz, MD:
Of the 497 patients enrolled, there were 368 pregnancies and 317 patients who gave birth at least once. The majority were singletons and the majority breastfed. Complications were not common in the offspring.
Sara A. Hurvitz, MD:
In all, I think these data add to the accumulating evidence that indicate that it is probably safe for select patients with HR-positive breast cancer who are younger and wish to achieve a pregnancy to briefly interrupt their ET to attempt to achieve a pregnancy. It is feasible, and many of the patients were able to achieve a pregnancy and successfully have a baby. There are some important points to note, though, as we advise patients. These tended to be lower-risk patients with earlier-stage disease. We did see higher rates of recurrence in patients with larger tumors and node-positive tumors, so it is important to keep that in mind as we advise our patients. Also of importance, these patients did not go straight from surgery to attempting pregnancy; they had a period of at least a year and a half of ET before that interruption in therapy.
Joyce O’Shaughnessy, MD:
I agree that these are very welcome data. I have been using them a lot in my clinic since the San Antonio conference, telling women that there are data that look reassuring. There are some caveats. The follow-up is relatively short at approximately 41 months, given that this is a disease that plays out over a long time, and the first 5-10 years are particularly critical.
As you also point out, these findings really do not apply to patients with higher-risk disease. It would be helpful to get some insight into those patients who did recur. For example, were these patients who were off ET for a longer portion of the permitted 2 years? Patients who were not pregnant by 1 year were encouraged to undergo a fertility assessment. Although those numbers are likely small, it would be useful to get some sense of the safety of that approach. Finally, some patients declined to resume their ET because of prolonged nursing, continued pursuit of pregnancy, or other reasons. Did this contribute to recurrences? The onus is still on us to optimize ET at every step for our patients, which includes minimizing time off. Having said that, I agree with you that it is encouraging to see that those who did get pregnant may have a better cancer outcome, although a multivariable analysis is difficult in a small population. We have to still be very careful.
Sara A. Hurvitz, MD:
In summary, we saw numerous very interesting trials in early breast cancer. The monarchE follow-up data showed that iDFS and DRFS continued to show benefit with the use of adjuvant abemaciclib in high-risk, HR-positive breast cancer, with follow-up data out to 4 years further supporting this clinical strategy. Of importance, the Ki-67 value continues to be prognostic but not predictive. Hopefully, we will see a change in the abemaciclib labeling, although as Dr. O’Shaughnessy noted, the current guidelines support its use in our high-risk patients regardless of Ki-67 level.
Editor note: The FDA has removed the requirement for Ki-67 testing for the use of adjuvant abemaciclib combined with endocrine therapy in patients with HER2-negative, node-positive, early breast cancer at high-risk for recurrence.
The TRIO-US B-12 TALENT trial gave us an early glimpse of T-DXd activity in the neoadjuvant setting for HER2-low, HR-positive breast cancer. These preliminary data are very interesting and promise to bring us a lot more biomarker data as patients undergo surgery. Perhaps an additional treatment arm in which chemotherapy is sequenced with T-DXd would help inform the design of a larger adjuvant study in this setting for high-risk, HER2-low, HR-positive breast cancer.
The OPBC-04 clinical trial reports some encouraging data that early axillary recurrence after omission of a full axillary dissection is rare in patients with node-positive disease who are able to convert to node-negative disease with neoadjuvant therapy. We will be watching for longer follow-up on this large, multicenter, retrospective study.
Finally, the POSITIVE trial gives us some early positive evidence that a pause in ET for our younger patients who would like to achieve pregnancy may be feasible and safe. But as Dr. O’Shaughnessy points out, we need longer follow-up as well as a closer look at other factors that may be influencing the risk of recurrence to help us better select patients who would be good candidates for this approach.
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