Hartkopf: With the results of the NATALEE study presented by Dr. Slamon, another CDK4/6 inhibitor becomes part of adjuvant therapy for early HR+/HER2- breast cancer. How do you assess these data, also against the background of the already existing approval of abemaciclib, and which patients in the adjuvant setting will you treat in future with a (and with which) CDK4/6 inhibitor?
Janni: In my opinion, the strength of the NATALEE data is the new treatment option in intermediate risk patients beyond the high-risk situation represented by the MonarchE cohort. In future, I will consider treating these patients according to the trial. In our high-risk patients, we will have two treatment options in future, which are great, given different toxicity profiles.
Banys-Paluchowski: This is a very exciting question. Obviously, the number of patients who are potential candidates for a CDK4/6 inhibitor in the adjuvant setting will increase after NATALEE trial. One needs to keep in mind that the inclusion criteria of the 2 phase 3 studies (MonarchE for abemaciclib and NATALEE for ribociclib) were quite different. While abemaciclib can be recommended only to patients with high-risk node-positive disease, ribociclib is an option for all N+ as well as selected node-negative cancers.
Bidard: In France, the presentation of NATALEE (and the update of MonarchE) had an immediate effect: the start of reimbursement for abemaciclib as an adjuvant, which had previously been refused. Ribociclib should also become available in the adjuvant setting in the coming year. For the higher-risk core population, which is included in both trials, we will eventually have two molecules that can be used, with a benefit that appears to be fairly similar, keeping in mind that the follow-up period is longer in MonarchE. The durations vary (2 vs. 3 years), and side effects are quite different. The choice between the two agents will mostly depend on patient and physician experience. In the medium risk population that is specific to NATALEE (i.e., patients not eligible to MonarchE), the use of ribociclib appears useful, keeping in mind the limited follow-up and number of events. The next question is then to test whether de-escalating chemotherapy could prove safe in these intermediate risk patients, most of whom received adjuvant chemotherapy.
Thomssen: NATALEE is a confirming study to MonarchE reassuring the use of CDK4/6 inhibitors in early breast cancer patients. In addition, we have now evidence to also treat high-risk node-negative patients and those with less extended lymph node infiltration with ribociclib. For patients with higher tumor stages, two options will exist and choice of the drug can be based on side effects. However, some fine-tuning might be necessary with regard to the presented data, e.g., one can discuss whether node-negative breast cancer with Ki-67 of 20% should be considered as high-risk disease.
Hartkopf: Dr. Tarantino presented retrospective data from the SEER registry on patients with small triple-negative early breast cancer. Do these results have an impact on your treatment practice and is there a threshold in terms of tumor size at which you would not use chemotherapy?
Janni: I am cautious to translate the results directly into daily practice given the retrospective nature of the analysis. In very small tumors <5 mm, the AGO recommendations already suggest the omission of chemotherapy, but in larger tumors, I will still recommend chemotherapy – although considering additional co-factors, e.g., age, co-morbidity, tumor biology, etc.
Banys-Paluchowski: While there are several issues regarding the SEER database that can be criticized (e.g., lack of information on recurrences and limited reliability of the data on received treatment), the study is an important step towards de-escalating systemic therapy in patients with low tumor load. I would be willing to implement these study results into my clinical practice and will discuss adjuvant chemotherapy in pT1b cases on an individual basis.
Bidard: This retrospective analysis documents in almost 1,000 patients that pT1aN0M0 TNBC have an excellent outcome, with 98% recurrence-free survival at 5 years (most patients had no chemotherapy). This is line with most current guidelines (no chemotherapy for pT1aN0M0 TNBC). Tumors are larger than 5 mm are associated with more relapses at 5 years, and the retrospective nature of the study prevents any direct assessment of the benefit of adjuvant chemotherapy – I would therefore keep chemotherapy as my default option, depending on the patient age and comorbidities. To move forward on that subject, beyond the tumor size and TNBC pathological subtypes, biomarkers may help isolating eTNBC patients who really do not benefit from chemotherapy; high TILs appears as a good biomarker for such future attempts.
Thomssen: These data add to the existing data and reinforce my decision to omit from systemic therapy – adjuvant or neoadjuvant – in eTNBC with a diameter of 5 mm and less. However, in eTNBC with a diameter of 5 mm–10 mm, there are already data showing a relevant effect of adjuvant systemic therapy with a median HR of 0.7, so I would always discuss adjuvant therapy in these patients, as some valid data from a single center consistently showed a less favorable disease course in patients with pT1b eTNBC.
Hartkopf: F-FDG PET imaging enables the identification of patients with early HER2-positive breast cancer who have a high likelihood of responding to HER2-targeted therapy. In the PHERGain study, Dr. Cortes showed that 1 in three patients could safely be spared from chemotherapy if there were both, a response on PET-CT and a pCR on histopathology. Would you already implement such a strategy and if so, do you see any challenges?
Janni: The PHERGain study is an important de-escalation study suggesting that we could spare one third of our HER2-positive patients from chemotherapy. Considering the burden of regimens such as TCHP, this is an important step forward, in my opinion. However, PET-CT is not an established standard yet in Germany, and we might want to wait for the data of the phase 3 study with MRI imaging. If this will turn out with similar results, I probably will change my practice.
Banys-Paluchowski: I am very cautious about this study. While it shows us that a chemotherapy-free regimen is a feasible option for some of our patients, uncertainty remains as to how to identify them. We should not forget that patients randomized to the experimental arm had worse clinical outcomes than those receiving neoadjuvant chemotherapy. Therefore, I consider this study interesting but not practice changing.
Bidard: We knew before PHERGain that some HER2+ eBC patients can achieve pCR with dual HER2 blockade and no chemotherapy. What PHERGain shows is that it is possible to pick, after 2 cycles of dual HER2 blockade (and no chemo), patients who are responding the most to this strategy. Unfortunately, patients who are found as not responding to chemo-de-escalation are apparently doing bad, and the time they lost on dual HER2 blockade was apparently not caught up by rescue chemotherapy: there was numerically more relapses in Arm B (patients initially allocated to de-escalation) than in Arm A (patients treated per SoC). While the PHERGain strategy should not, in my opinion, be considered for implementation in routine practice, a next step is likely to use a truly predictive biomarker, such as HER2 level of expression (“HER2-enriched” tumors…), in addition to monitoring tool (PET-CT, and/or ctDNA).
Thomssen: It is a fascinating concept, and the idea of treating with antibodies alone is convincing and the logical future step in the treatment of HER2-positive early breast cancer. However, the data are not yet mature, and as Dr. Cortes also noted, a phase 3 trial is needed to prove the reliability of this approach. In summary, this approach is not yet ready for routine use.
Hartkopf: In the SONIA trial, Dr. Gabe Sonke showed that in patients with HR+/HER2-metastatic breast cancer, PFS2, and OS were independent of whether palbociclib was given in the first line of therapy, followed by endocrine monotherapy, or in the second line of therapy, after prior endocrine monotherapy. Does this mean to you that we should wait until disease progression to use a CDK4/6 inhibitor, as this approach would reduce the cost of therapy and toxicity?
Janni: In most patients: NO! The major limitations of this study were the choice of palbociclib as CDKI, which has not shown to lead to overall survival benefit, when used in first line, and also the fulvestrant single-agent treatment after CDKI, which is not standard of care in Germany. However, this preciously provoking study reminds us that one size does not fit all, and there will be patients in whom we can justify single-agent endocrine therapy first line with more peace of mind. The right patient selection will be the challenge.
Banys-Paluchowski: This is an important study for low-income countries and countries without health insurance available to all patients. In those countries, the financial toxicity of therapy is an important factor that needs to be considered. In Germany, however, these study results are not likely to change the clinical practice.
Bidard: Several evolutions in the field are unfortunately preventing SONIA from being practice changing in all patients: the trial was conducted with palbociclib; fulvestrant single agent is not anymore regarded as an appropriate post CDK4/6i second-line regimen, etc. However, for patients who are not good candidates for CDK4/6i (elderly or frail patients) and for whom the use of a PIK3CA/AKT/mTOR inhibitor in 2nd line seems unrealistic, I think we could use SONIA to justify postponing the use of CDK4/6i to the 2nd line. Also, SONIA is really reassuring for patients who have no health insurance and who can afford paying CDK4/6i for several years.
Thomssen: No. The study addresses a really important clinical question. However, we should wait until the full publication is available. Not all the details have been presented; for example, we do not have sufficient information on how many patients were lost during first-line phase because no data on overall survival during the first-line phase were presented. In such sequential studies with randomization upfront, you would usually lose some patients before switching to the planned second step.
Hartkopf: In the PADA-1 trial, Dr. Bidard presented an interesting approach on how the use of ctDNA to detect ESR1 mutations can improve PFS of first-line endocrine-based therapy. What is the value of determining ESR1 mutations in clinical practice and would you now routinely perform ctDNA measurements in your patients?
Janni: This intriguing trial reminds us that with the ESR1 mutational status we have a biomarker which indicates which endocrine treatment is more or less efficient. As this is an acquired mutation, liquid biopsy is the best way to determine, and I am convinced that this will become increasingly standard of care, especially when we look at the perspective of oral SERDs in future.
Banys-Paluchowski: The PADA-1 study shows that switch to another therapy line following a molecular progression (and not a radiological or clinical one) may be a feasible strategy. However, there are several open questions that remain to be clarified before these results can be implemented into the clinical practice. Should patients be switched to fulvestrant or rather an oral SERD such as elacestrant? What is the optimal method of measuring ESR1 mutations? And most importantly, would patients without detectable ESR1 mutations in the blood also benefit from a therapy switch?
Bidard: There are two topics here: ESR1mut and the PADA-1 strategy. It is well established that ESR1 mutations are targetable with SERDs and several new oral SERDs are being developed. In France, elacestrant is available through an early access program, in ESR1-mutant ER + HER2-mBC pretreated with CDK4/6i. We are at the beginning of the study, yet subgroup analyses of EMERALD showed satisfactory mPFS in patients who received 1st-line CDK4/6i for more than 1 year (which is a very frequent feature). The second point is the PADA-1 strategy: does it matter to target a resistance-associated mutation as soon as it becomes detectable in blood? Our PFS data suggest the PADA-1 strategy really increases the efficacy of SERD. The switch also comes with interesting “side” benefits, such as extending the time on CDK4/6i, and limiting the number of actual disease progressions, which could be symptomatic. Although interesting, the novelty of PADA-1 design and the limited number of patients prevented PADA-1 from being practice changing. I am confident that the ongoing SERENA-6 trial, which is directly stemming from PADA-1, will confirm our findings.
Thomssen: The PADA-1 trial is a revolutionary study testing the approach of changing the treatment of mBC at an early stage – in this case at the appearance of ESR1-mutated ctDNA – instead of taking the traditional route and changing the treatment as late as possible, e.g., at disease progression. However, such a fundamental change in treatment approach should be validated by a confirmatory study. Moreover, after adjuvant AI therapy, patients have an approximately 30% chance of carrying an ESR1 mutation; in these patients, it should be studied whether they should not be treated with a SERD upfront anyway, rather than trying AI again.
Conflict of Interest Statement
W. Janni: no conflict of interest to declare. M. Banys-Paluchowski: Honoraria for lectures and participation in advisory boards: Roche, Novartis, Pfizer, pfm, Eli Lilly, onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Medical, Syantra, Resitu, Pierre Fabre, Exact Sciences. Study support from: Endomag, Mammotome, Merit Medical, Sirius Medical, Gilead, Hologic, Exact Sciences. Travel reimbursement: Eli Lilly, Exact Sciences, Pierre Fabre, Pfizer, Daiichi Sankyo, Roche. F.C. Bidard: consulting or advisory board: Pfizer; AstraZeneca; Lilly; Novartis; Menarini; Sanofi; GSK; Rain Oncology; Caris Life Sciences; GE Healthcare; Exact Sciences; Gilead. Speaker’s bureau: Pfizer; Novartis; AstraZeneca; Roche; Lilly; Rain Oncology; Daiichi Sankyo; Menarini-Stemline. Research funding: Novartis; Pfizer; Menarini Silicon Biosystems; ProLynx; Merck KGaA; GE Healthcare. C. Thomssen: no conflict of interest to declare.
Prof. Dr. med. Andreas Hartkopf
Department of Obstetrics and Gynecology
University Hospital Tübingen
Prof. Dr. Wolfgang Janni
Department of Obstetrics and Gynecology
University Hospital Ulm
University of Ulm
PD Dr. Maggie Banys-Paluchowski
Department of Obstetrics and Gynecology
University Hospital of Schleswig Holstein
Prof. Dr. Francois-Clement Bidard
Department of Medical Oncology
Institut Curie and Université Paris Descartes
Prof. Dr. Christoph Thomssen
Gynecology, Martin-Luther-University Halle-Wittenberg