Endocrine therapy alone or in combination with a CDK4/6 inhibitor can be considered for the frontline treatment of patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, explained Christos Vaklavas, MD, who added that although available data have relegated treatment for actionable mutations such as PIK3CA and ESR1 to the second-line setting, there may be room for biomarker-driven therapies up front.
“The field is very dynamic right now, with the introduction of the orally bioavailable selective estrogen receptor degraders [SERDs] and covalent antagonists. Biomarker-driven treatment choices hold great promise [for patients],” said Vaklavas. “[The field] is going to be completely different a year from now.”
In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on breast cancer, Vaklavas, a physician leader in breast cancer at Huntsman Cancer Institute, discussed the progress that has been made in metastatic HR-positive, HER2-negative breast cancer and potential pathways forward for therapeutic sequencing.
OncLive®: How have CDK4/6 inhibitors affected the natural history of HR-positive, HER2-negative breast cancer?
Vaklavas: There has been a groundbreaking change with the introduction of CDK4/6 inhibitors that have revolutionized the first-line management of metastatic HR-positive, HER2-negative breast cancer. This introduction has cast a very large shadow on the genomic evolution and natural history of metastatic breast cancer. Therefore, the field is starting to define the best pathway and the best algorithms for second-line therapy after progression on CDK4/6 inhibitors.
How is the genomic heterogeneity of the disease informing treatment approaches?
For the longest time, we were treating this disease as a single entity. However, more and more, we’re realizing that there is phenotypic and genotypic diversity. When you draft the guidelines, you want [them to be] one-size-fits-all. Yet clinicians’ experiences, perspectives, and intuitions have a major role in navigating the guidelines and making the appropriate treatment choices.
On the one end, the disease [can be] exquisitely sensitive to endocrine blockade, in which you can probably de-escalate treatment and forego a CDK4/6 inhibitor in the first-line setting. On the other end, [the disease can be such that] the estrogen receptor [ER] is just there and is definitely not driving the disease. Therefore, you cannot anticipate reaping good dividends with hormonal blockade and a CDK4/6 inhibitor. In that case, you may want to start with chemotherapy. I illustrated a case where the ER was just there, but the patient wound up having an activating mutation in the HER2 receptor. From the intrinsic subtype perspective, he actually fell into the HER2-enriched subtype rather than the luminal [subtype] as someone would anticipate.
When are CDK4/6 inhibitors best utilized? What does treatment look like after a patient’s disease has progressed on a CDK4/6 inhibitor?
Regarding choosing a CDK4/6 inhibitor up front compared with reserving it for the second-line setting, there is no clear answer. There is a large clinical study that is being conducted in The Netherlands to answer this question of whether [giving a CDK4/6 inhibitor in the] first- or second-line setting is [more] advantageous. So, more to come in the future about this. In some patients that have oligometastatic disease, 1 or 2 sites involved, or bone involvement only, who have a recurrence after a very long interval of remission, I think it is justifiable to start with a hormonal agent alone and reserve the CDK4/6 inhibitor for the second line.
Recently, we were revising the follow-up that’s needed for [patients on] CDK4/6 inhibitors. [CDK4/6 inhibitors have] very expensive follow-up, with complete blood counts and electrocardiograms for ribociclib [Kisqali] that we do for a long time. The evidence clearly suggests that using them in the first-line setting is advantageous and [confers] a progression-free [survival] benefit and potentially an overall survival benefit.
In terms of the second question, the field realizes that there’s huge diversity [regarding] the pathways and the mechanisms of resistance that arise under this therapeutic pressure of hormonal agents plus CDK4/6 inhibitors. [These] mechanisms for nearly 60% [of patients] is unknown. There’s a huge knowledge gap for these particular patients. An outstanding question is: Once a patient progresses on a CDK4/6 inhibitor, do you continue it, or do you stop it? Three clinical trials, one of which called MAINTAIN and is led by my very good friend, Kevin Kalinsky, MD, MS, of Emory University, will address whether [keeping] the CDK4/6 inhibitor is advantageous.
Another outstanding question is if you identify an activating mutation in HER2, which can arise under the therapeutic pressure of endocrine therapy plus CDK4/6 inhibitors, is giving a HER2-blocking agent[, such as tucatinib (Tukysa), neratinib (Nerlynx), lapatinib (Tykerb)] more advantageous than transitioning to fulvestrant? We don’t know.
How does the presence of mutations, such as ESR1 and PIK3CA, influence your treatment decisions?
Having the ESR1 mutation can steer the clinicians away from choosing an aromatase inhibitor [AI] or tamoxifen. We know that these mutations confer resistance to those agents. However, there is a French study, [where the investigators performed] comprehensive circulating tumor DNA [ctDNA] testing in the first line and identified these mutations in a small fraction of patients. Quite interestingly, these patients went on to receive an AI. In some patients, they found that those mutations disappeared [over] the course of treatment. In others, they persisted, and those patients had worse outcomes. Therefore, we don’t know what to do [if patients have an] ESR1 mutation in the first-line setting.
In the second-line setting, the fields feels that we can safely steer clear of the AIs and transition to SERDs like fulvestrant [Faslodex] or one of the investigational agents.
PIK3CA mutations are very interesting. There’s some discrepancy between identifying this mutation in ctDNA vs the tumor. Based on the [primary and updated] results of the SOLAR-1 study, [we know that] once you find this mutation in the second-line setting, you can get a very good benefit by ending alpelisib [(Piqray) to endocrine therapy].
Thankfully, this mutation seems to be present in the beginning and doesn’t seem to disappear over the course of [treatment with] an AI and a CDK4/6 inhibitor. On the one hand, you have this opportunity to give second-line alpelisib, and on the other hand, [it makes you wonder whether we should be giving] alpelisib in the first-line setting. However, we don’t have an answer to that question right now.
Where do PI3K inhibitors fit into your own treatment sequencing?
Alpelisib [will be used] in the second-line setting and thereafter [because] the SOLAR-1 and subsequently the BYLieve study was done in patients with PIK3CA mutations who progressed on CDK4/6 inhibitors. Other mechanisms upregulate this pathway, [such as those in] the PI3K/ AKT/mTOR pathway probably at a transcriptional or even at a translational level, but these have not been defined.
If you look at the curves, there was a small benefit with alpelisib, though not statistically significant, in patients that did not have the PIK3CA mutation. For the time being, only [patients with] actionable PIK3CA mutations either in the tumor or in ctDNA [should receive alpelisib] in the second-line setting.
Could longitudinal monitoring help to answer what the optimal therapy is to give in the second-line setting?
Definitely. We have to define the genomic evolution of the disease and capture its heterogeneity and then see how best to treat [patients in the] second line. If patients have an actionable mutation, do you go after that actionable mutation? [What do you do] if you have an unknown mechanism [of resistance]? ctDNA does not tell the whole story.
Biomarkers hold great promise. For the time being, other than ctDNA, or even the DNA of the tumor, we don’t have a clear other biomarker.
What is your advice to your fellow clinicians who are navigating this landscape?
Number one is to stick with the same therapy for as long as possible. We want to treat metastatic HR-positive, HER2-negative breast cancer as a chronic disease. Our patients are running a marathon, and you don’t win the marathon on the very first turn. You have to save your stamina. Try to push back chemotherapy as far back as possible. If the tumor marker is rising, you can follow your patient a little bit more closely, but at the same time, if there are no symptoms suggestive of clinically progressive disease, or there’s no radiographic evidence of progressive disease, save your bullet.
Lastly, I wish we could perform ctDNA testing in every line, but we can’t. Our patients are entitled to only 1 genomic test in their cancer trajectory. Your next line of therapy should be something new—something novel that the cancer has not seen. You change one thing at a time, you don’t change both treatments, if, for example, you give your patient an AI plus a CDK4/6 inhibitor up front, then your patient progresses, you don’t find an actionable PIK3CA mutation, then, in the second-line setting, it is reasonable to transition to fulvestrant plus or minus the CDK4/6 inhibitor. If the patient progresses on fulvestrant, then it is reasonable to exemestane plus an mTOR inhibitor. Try to change one thing at a time.
Always refer your patients for clinical trials. In our institution, we intercalate the transition between the hormonal agents when the patient exhausts all combinatorial therapies or monotherapies, and the time has come for chemotherapy. Many novel agents are vying right now to go into this space, including novel SERDs, covalent agonists, and antibody-drug conjugates. Those agents can safely push back the chemotherapy a little bit further, which is very clinically meaningful for our patients.