Advancing Care for Metastatic Breast Cancer: Oncology Pharmacists Tackle Innovation, Biomarkers, and Operational Hurdles

During a Pharmacy Times Clinical Forum held in Dallas, Texas, a panel of oncology pharmacists discussed challenges and recent advancements in ESR1-mutated metastatic breast cancer (MBC) management, biomarker testing, and operational hurdles. During the discussion, panelist Virali Patel, PharmD, MBA, a pharmacy manager at Texas Oncology, noted that there has been a scarcity of innovative therapies for advanced-stage cancers compared with earlier stages, leaving a gap in options for metastatic disease. According to Patel, current clinical research efforts are seemingly concentrating more on fine-tuning adjuvant therapies or optimizing existing regimens.

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“I feel like there are a lot of early-stage [therapies] and I don’t see that much in the metastatic or the advanced setting,” Patel said. “I feel like everything that started in metastatic—and this is common for a lot of metastatic [disease regimens]—they just move up front. I’ve heard a lot about early-stage [disease], but I don’t really know if there’s anything new and great to expect for advanced [disease].”

According to panel moderator Rose DiMarco, PharmD, BCPS, BCOP, clinical trials in MBC have encountered obstacles, such as trial closures due to toxicity, leaving limited options for innovation in this space. However, phase 1 programs and basket trials continue to explore new possibilities.

“Other diseases are definitely having a moment, I think. For [breast cancer], we do have lots of trials [in early-stage disease], and lots of tweaking [of existing therapies], like in the adjuvant setting, chemotherapies, and doing different things there, but not a lot of movement,” said DiMarco, an oncology pharmacy manager at Sidney Kimmel Cancer Center, Jefferson Health, in Philadelphia, Pennsylvania. “We have a big phase 1 program, so we’ve got some of those, but not really anything specifically for MBC—but a lot of basket trials, and stuff like that.”

Biomarker Testing

Another significant theme was the variability in approaches to biomarker testing across institutions. Biomarker testing at progression was emphasized by panelists as critical, given the dynamic nature of MBC, as tumor biology can evolve quickly. However, although biomarker testing at progression is commonly physician-driven, a lack of standardized procedures for biomarker testing complicates processes, which can require additional support from pharmacists. The emergence of precision medicine teams has helped streamline certain aspects of the biomarker testing process, such as test facilitation and therapy guidance, but these practices vary widely among sites, according to the panelists.

The panelists also noted that electronic medical records (EMRs) present an untapped potential for optimizing biomarker testing. Current systems often rely on clinical review teams to identify gaps in testing through chart reviews and manual prompts. Although artificial intelligence (AI) could enhance these systems by recognizing patterns and suggesting tests, barriers, such as alert fatigue and limited system interoperability, can hinder implementation. For this reason, integrating AI into EMRs will require thoughtful design to avoid overloading health care providers with notifications.

The panelists also noted that guidelines, such as those from the National Comprehensive Cancer Network (NCCN), are crucial to help standardize biomarker testing recommendations for breast cancer, but they currently lack robust guidance from NCCN and others, especially in comparison with current lung cancer guidelines. Enhancing these resources and integrating better EMR functionalities potentially could drive more consistent biomarker testing, according to the panelists. Additionally, fostering interconnectivity among diverse EMR platforms could streamline care for patients transitioning between health systems, reducing information gaps and delays in treatment.

Participants also highlighted operational inefficiencies, particularly in EMR systems, which struggle to integrate seamlessly with testing platforms. Standardizing reporting formats from various testing companies and improving EMR interoperability were cited as crucial advancements needed to simplify workflows and reduce manual data entry errors. The reliance on third-party systems for payer-directed testing further adds complexity, often necessitating manual reconciliation of information if mistakes occur, the panelists explained.

“Physicians can misread test results and accidentally put in mutation positive [when it wasn’t],” said Astrid Slaughter, PhD, RPh, a pharmacy manager at Texas Oncology Round Rock. “So we compare all the data [to confirm accuracy], and sometimes we’ll notice an error and say, ‘Hang on—this patient didn’t have an AKT mutation, but you marked it positive.’ It still takes a lot of manual reconciliation of information right now.”

Liquid vs Tissue Biopsy

During a discussion on liquid vs tissue biopsy considerations, the panelists emphasized that payers’ policies on reimbursement significantly influence testing practices. Additionally, they noted that lobbying for changes to these practices has proved challenging. In clinical scenarios looking at detecting ESR1 mutations, liquid biopsies are generally prioritized due to their ease of administration and patient acceptability. Liquid biopsies are particularly useful during disease progression or when traditional tissue sampling is difficult.

However, tissue biopsies remain indispensable when liquid biopsies fail to detect actionable mutations or when clinical symptoms suggest discrepancies.

“If the patient is willing to get a fresh biopsy, I think we’re always going to try to do that. I usually don’t go back and look at previous results unless we have a new indication, and we’re trying to see if patients qualify for it,” DiMarco said. “I don’t know if that’s something that will continue as things get approved, but over the past couple of years with so many new approvals, I’ve just been like, ‘Oh my goodness, we have a new drug, let’s see who can be treated on this right now,’ so that’s been our go-to because it does take time to get fresh tissue.”

Emerging Challenges and Practices in Oncology Pharmacy

With significant challenges present in sequencing therapies, interpreting clinical data, and addressing patient-specific needs, the group emphasized the importance of baseline metabolic assessments, such as hemoglobin A1c, before initiating certain treatments. For example, alpelisib (Piqray; Novartis) can exacerbate hyperglycemia, so panelists noted that metformin is commonly prescribed prophylactically for patients with a body mass index over 25 or elevated HbA1c. Dosing begins conservatively at 500 mg daily, increasing as tolerated, with endocrinology referrals when necessary.

“Metformin 500 to start once a day, and you could go up to 1000 twice a day. After that, they go to endocrinology,” said Rochelle Horadam, RPh, BCOP, a breast medical oncology pharmacist at UT Southwestern Medical Center in Dallas. “Then it’s out of my scope [because] I don’t know those drugs well enough to make those decisions.” DiMarco noted that she will also work with colleagues in endocrinology at her institution to support treatment with alpelisib.

“Because I had such an awful time with alpelisib for several patients, I have a friend in endocrinology, and he is really interested in this pathway,” DiMarco said. “I was doing calls every other day [to patients], asking, ‘What did you eat today?’ and things like that, and it was just crazy, because we have a full-day breast [cancer] clinic, and I’m seeing 20 to 30 patients a day, but I have to call patients every day and ask what they’re eating because I just could not get their sugars under control. [I reached out to] endocrinology, and he has this rotating list of fellows who are really interested in this.”

Panelists also highlighted increasing insurance pushback as a challenge, particularly in relation to insurance requiring step-therapy protocols that do not align with best clinical practices. These pushbacks can restrict the timely adoption of new therapeutic indications, forcing pharmacists to navigate prior authorization processes.

Additionally, the panelists noted challenges relating to the complexity of administering multidrug regimens, particularly when managing adverse effects (AEs). Cyclin-dependent kinase (CDK) 4/6 inhibitors such as palbociclib (Ibrance; Pfizer Inc) are often chosen for their favorable tolerability profile compared with abemaciclib (Verzenio; Eli Lilly and Company), despite concerns about potentially sacrificing efficacy. AEs such as diarrhea, stomatitis, and QT prolongation pose significant management challenges, further complicated by limited real-world data.

“Palbociclib is the softer option. Maybe it is the best option, [and] in my experience patients tend to be on ribociclib and abemaciclib longer, so I am worried that we’re compromising some efficacy because of how toxic abemaciclib is on its own, but it’s still so early,” DiMarco said. “[Palbociclib] is still really young [as a therapy on the market], and I don’t have a ton of experience with it.”

DiMarco noted that clinical trials are investigating palbociclib as a combination therapy due to its toxicity profile, but Horadam expressed concern.

“I wonder if they picked palbociclib because it’s such a well-tolerated drug that most patients do well with, and abemaciclib has some really vicious AEs, especially the stomatitis associated with that drug,” Horadam said. “So maybe they pick palbociclib because it is pretty well tolerated compared [with] abemaciclib, with its AEs like diarrhea and QT prolongation. I honestly don’t know why they chose that drug, [though], and time will tell how effective it is.”

Real-World Data

The panel underscored the importance of integrating real-world evidence into drug development and regulatory processes. According to the panelists, drug design should prioritize patient adherence and feasibility, particularly for complex regimens involving oral and intravenous therapies. Moreover, the panelists advocated for greater regulatory oversight to ensure confirmatory phase 3 trials align with phase 2 approvals, safeguarding patient access without compromising safety or efficacy.

A recurring theme was also frustration with current clinical trial designs, which often lack comprehensive pharmacokinetic and dosing data. The panelists expressed concerns over the limited applicability of trial results to real-world patient populations, such as those with organ dysfunction or comorbidities. The absence of such data hampers evidence-based decision-making and necessitates reliance on anecdotal reports or smaller studies, according to the panelists.

The panelists also noted a lack of robust sequencing data for newer therapies, such as ESR1 inhibitors and PIK3CA-targeted agents. Although clinical intuition plays a role, there is no established best practice for prioritizing these therapies, according to the panelists. They noted that pharmacists often rely on physician preferences, patient characteristics, and genomic reports for these newer therapies. For example, allele frequency from next-generation sequencing results might influence therapeutic decisions. Additionally, the duration of prior responses to CDK4/6 inhibitors, such as abemaciclib, can guide the choice of subsequent agents such as elacestrant (Orserdu; Stemline Therapeutics, Inc).

Emerging Therapies

Emerging approaches, including proteolysis-targeting chimeras (PROTACs) and sarcoendoplasmic reticulum calcium ATPase (SERCA)–targeting therapies, present exciting pathways for refining endocrine resistance strategies. Additionally, biomarker-driven therapies are gaining traction, with FGFR inhibitors being a notable area of interest, despite toxicity challenges such as nail damage observed with drugs such as erdafitinib (Balversa; Janssen Biotech, Inc). Broad adoption of biomarker testing, such as RNA assays for mutations and fusions, is pivotal in identifying candidates for targeted therapies, though the panelists noted that some tests report lower identification rates for ESR1 or PIK3CA mutations compared with manufacturer claims.

The oral selective estrogen receptor degrader elacestrant, though relatively new, shows promise, with manageable adherence due to its simple regimen, according to the panelists. However, its use in later treatment lines for ESR1-mutated cancers may limit observable outcomes. Notably, the panelists all agreed that earlier intervention could provide better treatment outcomes with elacestrant, based on their clinical experience in practice, underscoring the need for additional postmarketing data to understand long-term implications, such as hyperlipidemia and cardiovascular risks.

“For ESR1 [MBC], you could do elacestrant first, but I don’t think we have sequencing data yet. I don’t know if there’s any best practice out there. I think it’s just ‘go with your soul’ here,” DiMarco said. “It’s not like BRCA data, where we know that the earlier you treat with a PARP inhibitor, usually things go better than later lines of therapy. We just don’t have that data right now.”

For example, in the EMERALD trial (NCT03778931), investigators evaluated elacestrant as a therapy for patients with advanced breast cancer with ESR1 mutations, especially following progression on CDK4/6 inhibitors. Approximately 50% of trial participants had detectable ESR1 mutations, and many had undergone multiple endocrine therapies. The standard of care comparison was monotherapy with another endocrine agent, raising questions about whether chemotherapy, such as capecitabine (Xeloda; Genentech, Inc), might have been a more robust comparator during that period.

Despite the trial showing a clear mechanism of action and benefits for ESR1 mutation–positive disease, its design faced critique for lacking investigative rigor. Clinicians noted the challenges of sequencing elacestrant with other agents such as PIK3CA inhibitors and its limited efficacy as a monotherapy. However, combinations with CDK4/6 inhibitors or novel agents such as alpelisib and everolimus (Afinitor; Novartis), are also being explored in clinical trials, potentially enhancing its clinical utility and offering alternatives to fulvestrant (Faslodex; AstraZeneca), a drug patients often dislike because of its painful administration.

According to the panelists, real-world application of elacestrant, which is often off-label, further supports a preference for combinatory use with agents such as abemaciclib or capecitabine over monotherapy. Ongoing trials and the development of synergistic combinations are anticipated to refine its role in treatment paradigms.

“In the pipeline there are a lot of trials out there looking at elacestrant in combination with other therapies, which I’m actually really excited about, because there is one looking at elacestrant in combination with alpelisib,” DiMarco said. “I think that could be really interesting, especially if the efficacy is as good as what we think it could be, and it may be better than fulvestrant, which our patients absolutely hate; no matter what you do, they just hate that injection. So anything to get rid of that would be great, in my opinion.”

The panelists noted that therapy with capivasertib (Truqap; AstraZeneca), an AKT protein kinase inhibitor, brings its own set of challenges, including severe rashes that can be debilitating without proper prophylaxis. Clinicians have adopted strategies such as having patients start antihistamines (eg, loratadine) a week before treatment to reduce the incidence of severe dermatologic reactions.

For the PI3K inhibitor alpelisib, which is often complicated by severe hyperglycemia, oncology teams face the dual challenge of addressing cancer while mitigating metabolic AEs. When treating with PI3K inhibitors generally, the panelists noted that communication between inpatient pharmacists and other health care professionals in the hospital is crucial for safely managing hyperglycemia. In severe cases, discontinuation of these agents does provide a rapid reversal of this AE, allowing for a safety net during treatment.

DiMarco noted that she has also looked into emerging therapies such as PROTACs, SERCAs, and selective estrogen receptor modulators.

“The PROTACs are basically an enzyme degrader. So, it’s similar, I think, to fulvestrant, but maybe a little more refined. A SERCA has something to do with calcium signaling and ATPase. It is a really interesting pathway...and I highly recommend you look into it, if you’re into biology,” DiMarco said. “But I think we’re going to see this [combination therapy] and [investigation into] novel biomarker targets—I’m super excited about FGFR. I feel like we’ve been hearing about FGFR for the past 10 years, and there has been no movement, but I think we’re finally getting close to actually seeing an FGFR inhibitor hit the market, not just in breast cancer either, so I’m really excited for that.”

Future Outlook

Despite notable challenges, the panelists expressed optimism about the growing arsenal of oncology drugs. They called for collaborative efforts among pharmaceutical companies, regulatory agencies, and health care providers to enhance trial designs, improve access, and refine treatment strategies. The discussion also underscored the critical role oncology pharmacists play when navigating the complexities of cancer care, balancing clinical evidence with patient-centered approaches, and advocating for systemwide improvements.