Chelsey Lindner, PharmD, BCOP

More than 2 million women worldwide received a diagnosis for breast cancer in 2020.

 Although breast cancer remains the second leading cause of cancer-related deaths among women in the United States, its early detection and improved treatment modalities have led to significantly increased survival rates.

Molecular testing, performed upon diagnosis to identify breast cancer subtype, provides insight into disease features and potential therapeutic targets. In general, breast cancer can be classified into 3 major subtypes: luminal, HER2 overexpressed, and triple negative.

Found in approximately 30% of breast cancers, HER2 overexpression historically has been associated with more aggressive disease and poorer prognosis.

 To determine HER2 status, results of immunohis-tochemistry (IHC) staining are categorized as 0 or 1+ (negative), 2+ (uncertain), and 3+ (positive). When HER2 overexpression is detected with a result of IHC 3+, HER2 blockade becomes an effective treatment strategy. Management of early-stage breast cancer (eBC) involves a combination of surgery, radiation, and systemic treatment; however, the latter currently is the mainstay of treatment for metastatic breast cancer (mBC).

Following the introduction of anti-HER2 treatments to the market, survival rates for patients with HER2-positive (HER2+) breast cancer significantly improved. Trastuzumab (Herceptin; Genentech USA, Inc), a fully humanized monoclonal antibody, was introduced in 1998 as the first anti-HER2 agent.

 It binds the HER2 receptor to block cell proliferation and promotes antibody-dependent, cell-mediated cytotoxicity. Through these actions, it enhances the antitumor effect when given with cytotoxic chemotherapy in HER2-overexpressing breast cancer cells.

 It is given as an intravenous (IV) formulation over 30 to 90 minutes every 1 or 3 weeks or subcutaneously every 3 weeks, depending on disease stage and formulation used.

Trastuzumab lowers the risk of relapse by 40% when given as adjuvant therapy for 1 year in eBC; it reduces the risk of death by 20% in mBC when combined with standard chemotherapy.

 Additionally, for more than 15 years, single-agent anti-HER2 blockade using trastuzumab-based chemotherapy served as the standard first-line approach for HER2+ mBC.

However, in 2015, results from the CLEOPATRA study (NCT00567190) demonstrated an overall survival (OS) improvement of almost 16 months when pertuzumab (Perjeta; Genentech USA, Inc) was added to the first-line trastuzumab-based chemotherapy regimen, establishing dual anti-HER2 blockade as the new standard of therapy.

Pertuzumab is also a humanized monoclonal antibody, but it works by binding a different region of the HER2 receptor that enhances HER2 inhibition in overexpressing breast cancer cells when given with trastuzumab.

Trastuzumab is the backbone of anti-HER2 treatment, yet the risk for cardiac toxicity may limit its use in certain patients. The FDA issued a black box warning for cardiomyopathy because of a 4- to 6-fold increased risk of symptomatic cardiac adverse effects (AEs; eg, left ventricular cardiac dysfunction, arrhythmias, hyper- tension, cardiomyopathy, cardiac failure, cardiac death) observed in clinical trials.

 For this reason, regular cardiac monitoring must be performed during therapy and for 2 years following completion of therapy.

Common challenges encountered with trastuzumab therapy include resistance and disease progression; the former is commonly noted in the mBC setting, and it typically develops within 1 year from the beginning of treatment.

 Because mBC is incurable, the disease eventually progresses in most patients on an initial trastuzumab-based therapy, and 40% to 50% of patients develop brain metastases. Anti-HER2 monoclonal antibodies typically are ineffective in treating central nervous system (CNS) progression because they cannot cross the blood-brain barrier (BBB). Despite resistance or progression, strong evidence supports continuing a trastuzumab-based regimen indefinitely.

Consensus on the optimal therapeutic selection beyond the second-line setting is lacking. Ongoing research is underway to evaluate various strategies, such as novel therapeutics and new combination regimens, to optimize therapy sequencing and to enhance the prevention and treatment of CNS metastasis.

Small molecule tyrosine kinase inhibitors (TKIs) that can penetrate the BBB are an attractive option for managing HER2+ mBC patients with brain metastases. Lapatinib (Tykerb; Novartis), one of the first TKIs studied in this setting, demonstrated synergistic activity when combined with anti-HER2 monoclonal antibodies.

 As a reversible inhibitor of both HER2 and EGFR receptors, lapatinib successfully inhibits the growth of HER2+ breast cancer cells and enhances anti-HER2 antibody-induced apoptosis. When lapatinib was given in combination with capecitabine (Xeloda; Genentech USA, Inc), fewer cases of CNS progression were observed.

Dosing of lapatinib generally ranges from 1250 mg to 1500 mg taken orally once daily.

 The main AEs reported include diarrhea, palmar-plantar erythrodysesthesia, nausea, skin rash, vomiting, and fatigue. Current use of lapatinib is reserved beyond first-line treatment; it is given in combination with capecitabine.

Neratinib (Nerlynx; Puma Biotechnology, Inc) is another TKI approved for use in the HER2+ breast cancer setting. It is FDA approved for extended adjuvant treatment of early-stage disease following adjuvant trastuzumab-based treatment, as well as for use with capecitabine in the metastatic setting following 2 or more prior anti-HER2 therapies.

 Neratinib is administered orally at a typical maintenance dose of 240 mg once daily. Treatment is typically initiated with gradual dose escalation or loperamide prophylaxis to improve the drug’s tolerability, as diarrhea is the most common grade 3 or 4 toxicity seen with neratinib.

Tucatinib (Tukysa; Seagen Inc) given with trastuzumab and capecitabine is a preferred third-line regimen for patients with systemic and CNS progression. It gained preferential status based on findings that this combination improved 1-year progression-free survival (PFS) by more than 20% compared with a trastuzumab-capecitabine combination.

 This improvement was
even greater in patients with brain metastases who were given tucatinib-trastuzumab-capecitabine vs those given trastuzumab-capecitabine (24.9% vs 0%), suggesting that CNS disease control is enhanced when tucatinib is part of the regimen. Typical dosing of tucatinib is 300 mg orally twice daily.

 The main AEs observed in the tucatinib-combination group included diarrhea, palmarplantar erythrodysesthesia, nausea/vomiting, and fatigue.

Novel antibody-drug conjugates (ADCs) are gaining traction as a unique treatment option for HER2+ mBC. Ado-trastuzumab emtansine (T-DM1; Kadcyla; Genentech USA, Inc) is a trastuzumab conjugate that consists of trastuzumab covalently linked to the cytotoxic agent emtansine.

 The EMILIA trial (NCT00829166) compared the use of T-DM1 with lapatinib-capecitabine, finding that T-DM1 treatment resulted in significant improvements in PFS (median, 9.6 months vs 6.4 months, respectively) and an OS benefit (HR, 0.62; 95% CI, 0.48-0.81; P = .0005).

 T-DM1 also offered a favorable toxicity profile when compared with lapatinib-capecitabine, with lower rates of grade 3 and 4 AEs (41% vs 57%) and lower incidences of diarrhea, nausea/vomiting, and palmar-plantar erythrodysesthesia. Given the efficacy and relative tolerability of T-DM1, it is the preferred second-line regimen following trastuzumab plus pertuzumab with a taxane (docetaxel preferred). Administration is via IV infusion every 3 weeks.

Fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo Company, Limited), administered as an IV infusion every 3 weeks, is the only other trastuzumab- ADC conjugate currently on the market. In breast cancer, its use remains reserved for administration beyond the third-line setting because of the lack of
OS data.4 Several other second-generation ADCs (SYD985, XMT-1522, ARX788, DHES0815A) are being developed to replace T-DM1 and produce a more durable, potent effect.

Margetuximab-cmkb (Margenza; MacroGenics, Inc) used with chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine) gained FDA approval in 2020 as a third-line treatment option for HER2+ mBC based on a 1-month improvement in median PFS and a 6% increased objective response rate when compared with trastuzumab plus chemotherapy.

 The initial dose is administered via IV infusion over 120 minutes, followed by 30-minute infusions every 3 weeks thereafter.

The bispecific, trifunctional antibody ertumaxomab (Rexomun; Fresenius Biotech GmbH) is still in phase 1 development, but it offers a new approach to cancer treatment.

 It works by targeting HER2 on cancer cells and triggers immune cells at the sites of metastases to form a tricell complex between tumor cell, T cell, and accessory cells. This complex then leverages natural immunologic mechanisms to initiate a humoral and cellular immune response to destroy HER2+ tumor cells.

Research is ongoing surrounding HER2-targeted vaccines. Early observations indicated that at early stages of disease, patients with cellular or humoral immune responses against HER2 had lower tumor development of HER2-overexpressing cells.

 An effective vaccine given in the eBC setting would reduce the need for frequent infusions or injections of standard treatment and help prevent disease recurrence.

 The main barrier to developing an effective vaccine at this point is immunologic tolerance against the HER2 antigen.

CDK4/6 inhibition is an emerging treatment option for HER2+ mBC. Given FDA approval and successful use of CDK4/6 inhibitors in the HER2-negative setting, these targeted agents may be beneficial in HER2+ mBC to block cell proliferation downstream of HER2.23 Additionally, these agents can cross the BBB and may be able to improve the prevention and treat- ment of HER2+ mBC brain metastases.

Currently, there are 3 CDK4/6 inhibitors on the market: abemaciclib (Verzenio; Lilly USA, LLC), ribociclib (Kisqali; Novartis Pharmaceuticals Corporation), and palbociclib (Ibrance; Pfizer Inc). All are orally administered, but ribociclib and palbociclib are taken on a cyclical basis (3 weeks on/1 week off), whereas abemaciclib is dosed continuously.

 The predominant toxicity experienced by patients on abemaciclib is diarrhea; corrected QT interval prolongation is primarily seen with ribociclib, and neutropenia is noted with palbociclib. Patient factors such as adherence, comorbidities, concomitant medications, and performance status must be considered when selecting one of these therapies for a patient.

As more data emerge, guidance on optimal treatment sequencing for HER2+ mBC may become available. Development of new therapies and combination regimens will improve patient outcomes and offer a more tailored approach to therapy. As enhanced treatment options emerge, patient preferences regarding cost, administration method, and overall therapy convenience may play a larger role in therapy selection.

, is a clinical pharmacist at Shields Health Solutions.

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Articles

New therapies and combination regimens may allow a more tailored approach.

Assessing the Landscape of HER2+ Breast Cancer Treatment

Many patients who use specialty medications to treat their disease states have complex conditions that are best managed by an interdisciplinary team. Mail-order pharmacies are not well positioned to provide comprehensive pharmacy services as part of the health-system care team.

 Specialty pharmacy programs aim to enhance their care and improve outcomes. Integrated health-system specialty pharmacies are able to provide high-quality services that have the potential to exceed those offered by traditional nonsystem specialty pharmacies, all while serving to financially benefit the health system. Yet resources to help overcome the new, unique set of challenges faced by integrated health-system specialty pharmacy are scarce. What follows are strategies used by the University of Rochester Specialty Pharmacy (URSP) in New York to overcome common challenges.

The University of Rochester started an integrated specialty pharmacy program in 2011 for patients with employer-sponsored insurance. The program was staffed by a pharmacist and a pharmacy technician. As of 2019, URSP has expanded to include all patients of the health system in multiple therapeutic areas, such as cardiology, dermatology, gastroenterology, hepatology, neurology, oncology, pulmonology, and rheumatology, and is now staffed by 18 pharmacists and 23 pharmacy technicians. Each patient is assigned a dedicated clinical pharmacist and an advanced care technician.

All clinical pharmacists must become board certified through the Board of Pharmacy Specialties in the area most pertinent for their area of practice. Additional pharmacist credentialing is supported and encouraged, such as the Multiple Sclerosis Certified Specialist through the Consortium of Multiple Sclerosis Centers. Twelve of the 15 clinical pharmacy specialists completed an American Society of Health-System Pharmacists (ASHP)—accredited postgraduate year 1 pharmacy residency program, and 3 completed a second-year residency program. All technicians must become certified through the Pharmacy Technician Certification Board within a year of hire.

Revenue generated by dispensing specialty prescriptions uniquely positions health-system pharmacies to support the development of robust clinical pharmacy programs that, in turn, enhance patient care. Although many departments struggle to provide long-term financial justification to hire additional staff for interdisciplinary teams, specialty pharmacies are able to support rapid growth and expansion.

Specialty prescriptions for patients within the health system are preferentially filled with URSP. An unanticipated challenge has been referral to outside (nonintegrated) specialty pharmacies by manufacturer assistance programs, insurances, and pharmacy benefit managers, which can negatively affect patient safety. Medications have been delivered to patients before optimal baseline screening or before other monitoring parameters were completed, or a wrong formulation has been dispensed. Despite patient preference to fill at URSP, this can result in patients or providers being contacted by the outside specialty pharmacy. This adds to significantly more time to manage patient care. Communication via email and over the phone with contacts at the manufacturer, as well as in-person meetings, email, and phone contact with administrative staff from our clinics, led to workflow optimization that clarifies when a patient prefers to use URSP. The multiple sclerosis team adopted a process of specifying that a benefits investigation was completed, and URSP is the preferred pharmacy on the manufacturer patient assistance program enrollment form.

Payer Restrictions and Limited-Distribution Drugs

Insurance restrictions and limited distribution of medications prohibit health-system specialty pharmacies from providing comprehensive pharmacy services to all patients. Obtaining accreditation through URAC or similar organizations is often required as part of the contract agreement for specialty pharmacies to gain access to limited-distribution drugs. URAC is an independent, nonprofit accreditation entity that provides accreditation and certification programs for health plans, health care management, health care operations, pharmacy quality management, provider integration and coordination, and organizational management. URSP employees took an active role in the process of creating policies and procedures to prepare for URAC accreditation, and no consulting services were used. Full specialty pharmacy URAC accreditation was obtained in 2016 and took less than 2 years. Involving our own employees in the accreditation process allowed URSP to develop policies and procedures that best meet our health system’s unique needs, obviating the need for outside resources that are less familiar with current workflows.

The inability to fill each patient’s specialty prescriptions within the health system has at times led to challenges in establishing clear roles and responsibilities for the URSP teams. Strategies to overcome such difficulties include improved communication and mutual support from the respective departments at the university. Meetings are held to introduce the team to the respective department and other interdisciplinary team members. URSP teams establish integrated specialty pharmacy services through regular communication via in-person meetings, phone calls, emails, and the electronic medical record (EMR) with administrative staff, social workers, nursing, advanced practice providers, and physicians. Workflow efficiency across the interdisciplinary team is continually reviewed in the format best suited to individual clinic needs and availability.

Preparation for URAC accreditation led to the formation of a specialty pharmacy quality management committee and the development of a formal consumer safety quality improvement project. A clinical pharmacy specialist with an interest in quality improvement serves as chair of the committee, which agreed that an optimal project would provide information to help support the improvement of the patient management program. Adherence was considered as a potential metric of interest for a quality improvement project, as it is frequently used as an outcome of interest in pharmacy because of ease of capture. However, this was not pursued because of consistently high adherence rates, with medication possession ratios exceeding 90% for most drugs dispensed by URSP.

URSP performed a patient safety quality-improvement project to assess adherence to physician-recommended monitoring for fingolimod after the pharmacists identified the opportunity for interventions as follows: The pharmacist follow-up schedule was adjusted to coincide with lab monitoring due dates, lab requisitions were mailed with refill deliveries, and pharmacists directly placed appropriate lab orders as needed. After an initial evaluation identified potential for improvement, prior interventions were made with a postimplementation comparison in a second and third cohort to ensure the result was sustained. The results of the project were shared as 2 posters at the ASHP Midyear Clinical Meeting and Exhibition and led to recognition from our health system at a symposium highlighting teams overcoming barriers to providing the highest quality of care to patients.

Our current, ongoing patient safety project is designed to improve patient care documentation through the creation of a comprehensive navigator in the EMR to eliminate the need for duplicate documentation in a separate specialty pharmacy software system.

URSP has consistently tried to standardize processes across therapeutic areas served while maintaining the necessary customization to meet the respective clinic workflows. Documentation in the EMR includes standardized templates with added customization components for different therapeutic areas.

 The format used within the EMR was designed to provide an optimal way to pull data for pharmacy outcomes research projects for both the overall program and specific disease states.

Because of the varied workflows of the ambulatory clinics, optimal integration of the clinical pharmacists into the team has required customization to add the most value to interdisciplinary teams we have joined. Standardization of clinical pharmacy services is detailed below.

Prior to and during therapy, a pharmacist provides medication education and counseling regarding adverse effect management and adherence, ensures the medication list is accurate, checks for drug interactions, and assesses for renal or hepatic dose adjustments. Initial medication teaching includes creation of a personalized adherence plan. The typical patient outreach timeline is prior to first fill, approximately 1 week after the anticipated start date, and at the time of scheduling the first refill, and then every 3 to 6 months for stable patients. The follow-up schedule is customized to meet patient-specific needs and regimens.

Customization is necessary to meet the needs of the different ambulatory clinics and provide the most value to the team. Clinical pharmacy services are provided in person at clinic visits as a separate pharmacist appointment or over the phone based on factors such as available space, frequency of patient follow-up, clinic schedules, and patient preference. Patient, provider, and employee satisfaction are evaluated annually and have been overwhelmingly positive with the program.

It is important to promote the ongoing development of best practices for integrated specialty pharmacies in academic health systems. Despite the challenges reviewed, we offer strategies to overcome these barriers. As specialty pharmacy continues to grow, we strongly encourage other programs to share best practices that help to optimize patient care within the unique area of specialty pharmacy.

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It is important to promote the ongoing development of best practices for integrated specialty pharmacies in academic health systems.