 It’s really important: the whole concept of why we worry about this and how we treat it and also prophylax. We’ll talk more about that later. Tiffany, there are clear risk factors, as Bill and Rita pointed out. Can you tell us a little more about the risk factors, how you monitor patients, and if the risk factors change either the chemotherapy you choose, the doses, or maybe your use of prophylactic growth factors?



 There’s a lot there to unpack. There’s a good body of literature that describes certain risk factors in patients who are more prone to develop neutropenia and cytopenias. Older patients, which is defined as 65 years or older; and patients who have some compromised organ function, like elevated bilirubin; or patients who have a low BSA [body surface area] or low body mass index or who have low baseline white blood cells in total are more prone to develop neutropenia. Additionally, patients with more advanced disease and more compromised bone marrow, who have been through multiple lines of therapy, are more likely to experience neutropenia with the subsequent regiment. We see that in breast cancer because we’re fortunate enough to treat patients in the sixth-, seventh-, or eighth-line setting, so clinical practice is where we’ll often see this.

There is even literature around certain SNPs [single nucleotide polymorphisms] that might predispose the neutropenia depending on the regimen being used. It is not actionable, but clearly, there are some predisposing factors. NCCN [National Comprehensive Cancer Network] gives guidance about the use of growth factors, and they divide the regimen by high risk, more than 20% likely to experience neutropenia, there’s a recommendation to use prophylactic growth factor.

There can be intermediate-risk regimens—10% to 20% neutropenia, where they say to consider the use of prophylaxis. But for a low-risk regimen of less than 10% risk of neutropenia, NCCN does not recommend prophylaxing, but that’s primary prophylaxis. Obviously, we’re all very comfortable once you’ve gone to treat a patient on, say, day 1 of a cycle, and they present with limiting neutropenia, then incorporating growth factor in that secondary prophylaxis setting is often preferred to keeping patients on schedule at an appropriate dose and intensity.

 Yeah, those are good points, and I like hearing about the NCCN Guidelines. As you know, soon after the start of the pandemic, we put in—I don’t know a pandemic revision for the NCCN growth factor guidelines, which suggested that you might ratchet down a little in terms of when you’d use growth factors to try to avoid hospitalizations or febrile neutropenia and just neutropenia in general. That was really helpful. The NCCN website has the pandemic recommendations, so that’s helpful.

Videos

Current recommendations by the National Comprehensive Cancer Network on chemotherapy-induced neutropenia prophylaxis, with special considerations for managing patients with cancer during COVID-19.

Guideline Recommendations for CIN Prophylaxis

Nick, we talk about hormone receptor–positive 

-negative breast cancer almost as 1 big category of patients—in fact, it’s the largest piece of the breast cancer pie. But clearly there’s heterogeneity, not only as we’ve been talking about in terms of molecular features but also clinical features. How do you think about managing this population based on other features, endocrine resistance, and visceral involvement?

 Absolutely. It’s a really important question. First, I want to finish a further discussion about how to manage patients with an 

 mutation, especially given the fact that MONALEESA-3 has data in the first-line setting, in that the endocrine partner in that study was fulvestrant. It may not necessarily be actionable, but it would potentially push you to choose fulvestrant as an endocrine partner in the first-line setting with a CDK4/6 inhibitor as the partner. Especially given that a subset analysis of MONALEESA-3 that looked at patients with other activating mutations showed around 14% of patients had 

 mutations. Patients, regardless of any of these mutations that were found, showed benefit with the addition of ribociclib to fulvestrant. It’s important to get at baseline for a number of reasons.

In terms of other more clinically driven prognostic factors, menopausal status would certainly drive your choice of the endocrine therapy backbone. But it’s also important to consider whether the patient has de novo vs recurrent disease. What was their disease-free interval? In prior adjuvant therapy, did they progress on endocrine therapy, or did they have a long disease-free interval once they had completed adjuvant endocrine therapy? Or were they totally de novo from the get-go? I also think about the patient’s tumor burden and sites of disease. Finally, I strongly consider their performance status and ability to adhere to different types of therapies.

One of the most important questions that has driven the decision to choose either an endocrine-based therapy combined with molecular therapy vs chemotherapy has been the presence of visceral metastases and visceral crises. It’s recommended in patients with visceral crisis who are presenting with organ dysfunction as a result of their visceral metastases, but you can still consider chemotherapy. There are emerging data showing that the overall response rate is comparable, if not better, in patients receiving a combination of endocrine therapy and a CDK4/6 inhibitor. As noted by the Young-PEARL study, there was slightly better overall response rate in patients who had received the combination of ovarian suppression AI [aromatase inhibitor] plus a CDK inhibitor as compared with capecitabine. Even in patients who have visceral metastases who may not be in crisis, I would still consider using the combination regimen.

That’s a great observation. We’ve all been able to recalibrate our thinking about endocrine therapy vs chemotherapy in the context of visceral disease in the CDK4/6 inhibitor era.

Considerations for approaching the treatment of HR-positive metastatic breast cancer through insights on key prognostic factors.

Management of HR+ mBC: Key Prognostic Factors

® titled “Clinical Advances in Hormone Receptor–Positive Breast Cancer.” I’m Dr Andrew Seidman from Memorial Sloan Kettering Cancer Center in New York. Joining me in this discussion are my colleagues Dr Aditya Bardia from Massachusetts General Hospital in Boston, Dr Dejan Juric from the Massachusetts General Hospital in Boston, Dr Nicholas McAndrew from UCLA [University of California, Los Angeles] in Los Angeles, and Dr Hope Rugo from UCSF [University of California San Francisco] in San Francisco.

Today we’re going to highlight a number of topics pertaining to the systemic therapy of hormone receptor–positive breast cancers and the impact of recent clinical trial data on clinical decision-making, including data from the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting. Without further ado, I’d like to get started on our first topic, which relates to the use of CDK4/6 inhibitors in metastatic breast cancer. Aditya, I’ll start with you. Can you talk a little about how and when you order molecular testing, or molecular profiling, for patients with hormone receptor–positive metastatic disease? Do you tend to do this at initial diagnosis of metastatic disease or at first progression?

 That’s a good question about the role of molecular testing or genotyping in hormone receptor–positive metastatic breast cancer. In my opinion, everyone with hormone receptor–positive metastatic breast cancer should have molecular profiling. When a patient has a diagnosis of metastatic breast cancer, a tissue biopsy is usually done. Potentially that specimen—besides getting ER [estrogen receptor], PR [progesterone receptor], and 

—could be sent for tissue-based genotyping. One could also consider plasma-based genotyping, but I tend to use plasma-based genotyping later on.

When a patient has disease progression on first-line regimens, like endocrine therapy plus a CDK4/6 inhibitor, that’s where the molecular genotyping could have an impact on therapy selection, particularly standard of care. In that setting, if a patient is not getting a biopsy, I routinely get plasma-based genotyping because it’s actionable. If we see a mutation in 

, the patient could potentially get alpelisib as standard of care. At our institution, we have a number of genotype-driven trials, so we tend to do genotyping serially. If an actionable alteration is seen, the patient could be triaged to that specific trial. For example, we have a trial with a PARP inhibitor for patients with somatic 

 mutation. There’s a trial with H3B-5942 for 

 Y537S alterations. Based on the alteration, it could help select the appropriate clinical trial.

 mutations are critical to know. Do you find 

 mutations actionable in your clinical decision-making?

 At our institution, yes, because we have specific clinical trials that preferentially enroll patients with 

 mutations. Outside the trial setting, although we don’t have level 1 evidence, I do find it helpful to get the results of 

 mutation, I would generally not use an aromatase inhibitor [AI]. Even if I’m considering exemestane and everolimus, if a patient has 

 mutation, I would do fulvestrant plus everolimus as standard of care.

 is the first precision oncology biomarker we have. We have a clear link with the use of alpelisib. 

 is critically important because this very example—exemestane plus everolimus—comes from a really nice analysis by Sarat Chandarlapaty of the BOLERO-2 data. They show that if you have a mutation in 

, which presumably makes the patient resistant to the aromatase inhibitor backbone, then the entire combination fails. Exemestane plus everolimus has really limited activity, at least based on that post hoc analysis in 

 mutants. This is just 1 example of how these mutations can be used as a positive predictive factor or biomarker, 

Dejan, that’s a great point, particularly when we lack a comparison between the BOLERO-2 regimen and a selective estrogen receptor down-regulator as far as I’m aware.

 mutations are not all the same. Some of them predict much more resistance than others. There’s a relatively poor understanding of that in terms of which ones matter. Some of the trials focus on using novel agents like SERCA [selective estrogen receptor covalent antagonist] in 

 mutations, or SERM [selective estrogen receptor modulator] lasofoxifene, focusing on specific 

Andrew D. Seidman, MD; Aditya Bardia, MD, MPH; Dejan Juric, MD; Nicholas McAndrew, MD, MSCE; and Hope S. Rugo, MD, discuss when it is appropriate to order molecular testing and the impact of testing on the treatment of HR-positive metastatic breast cancer.

Hope S. Rugo, MD, Helen Diller Family Comprehensive Cancer Center

Articles

Guideline Recommendations for CIN Prophylaxis

Management of HR+ mBC: Key Prognostic Factors

Role of Molecular Profiling in HR+ Metastatic Breast Cancer