Christa BraunInglis, MS, APRN, FNP-BC, AOCN

Involvement in clinical trails and referrals for patient enrollment are factored into the standard regimen of care for oncology advanced care providers (APPs) associated with academic centers and large cancer institutions. However, for those in the community setting several barriers to clinical research prevent APPs and their patients from taking part in experimental therapies.

According to data from the American Society of Clinical Oncology’s (ASCO) annual Practice Census, the number of oncology practices in the United States that have reported employing APPs increased from 52% in 2014 to 81% in 2017.

 A collaborative effort of ASCO, the American Academy of Physician Assistants, the Association of Physician Assistants in Oncology, the Advanced Practitioner Society of Hematology and Oncology, and the Oncology Nursing Society led to the identification of 5350 oncology APPs practicing in the United States, with the possibility of that number being close to approximately 7000.

APPs are involved in various aspects of care including roles as nurse practitioners (NPs), physician assistants (PAs), and other licensed, nonphysician providers such as clinical nurse specialists, certified nurse midwives, and certified registered nurse anesthetists.

 NPs are regulated and licensed by state nursing boards, although requirements for recertification and continuing education vary.

Furthermore, approximately half of states authorize NPs to independently practice without the need for oversight,

 and all states grant full prescriptive authority for NPs.

 Additionally, PAs are also regulated by state medical boards and must practice with a supervising physician, with extent of physician supervision varying by state.

 PAs are able to write prescriptions in all states.

APPs associated with institutions often fill roles in clinical trials as primary investigators (PIs), subinvestigators, study coordinators, and/or in the delivery and monitoring of therapies for patients. Results from a 65-item survey of attitudes, beliefs, and roles of oncology APPs in clinical research that was distributed via the Association of Community Cancer Centers (ACCC) demonstrated that oncology APPs are engaged and interested in clinical trials, and believe clinical research is important to improve care. However, they may not be used to their full scope.

Barriers include a lack of time, inadequate awareness of clinical trials, and underrepresentation on research committees. Recommendations for realizing the potential of APPs include research-related education, more complete integration as a member of the multidisciplinary cancer care team, and federal and state policy and regulatory changes.

“I work with 1 other oncologist, and we keep a portfolio of our available trials,” Christa Braun-Inglis, MS, APRN, FNP-BC, AOCN, of the University of Hawaii Cancer Center in Honolulu, told 

. “I’ll see a patient for treatment counseling, and I’ll assess whether or not [a patient is] eligible for either a treatment trial or symptom management trial that we have available. [The oncologist and I] have this workflow where she will introduce the trial during the consult and then I’ll pick up from there during the treatment counseling, and I will decide whether or not they are eligible and interested in enrolling in the trial.”

Braun-Inglis, who is the primary author of the study and an oncology NP, emphasized that her experience with clinical trials and clinical research has been in the community setting at the University of Hawaii Cancer Center. She explained that she functions within the National Cancer Institute (NCI)-sponsored Community Oncology Research Program, where she is PI on several quality-of-life, symptom-control cancer care delivery protocols. She also noted that she provides clinical support to the research coordinators.

Laura J. Zitella, MS, RN, ACNP-BC, AOCN, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said she works at an academic medical center with a very robust clinical trials program. “My primary role is the clinical care of patients, and in that role I take care of patients who are receiving standard-of-care treatments,” Zitella said. “But I also take care of patients who are enrolled in clinical trials. I am a subinvestigator on clinical trials that are related to the patient population that I care for.”

Zitella, a hematology/oncology NP, said she includes clinical trials in treatment discussions with patients and communicates with the primary trial investigator and the clinical research coordinator to enroll patients in trials. “I am involved with consenting and performing research procedures, and ordering study drugs, and all of the other processes that go along with being [enrolled in] a clinical trial,” she said. “It’s very common for APPs at academic medical centers to be involved with clinical research and to be subinvestigators on clinical trials for the patient population that they take care of.”

Lisa A. Kottschade, MSN, APRN, CNP, an NP at Mayo Clinic in Rochester, Minnesota, said, “Oncology APPs can play a number of roles in clinical research. Some things that come to mind include patient recruitment and management on clinical trials [or] serving as principal investigators on certain trials and coinvestigators. Additionally, APPs can participate in NCI cooperative groups and institutional research committees. I belong to our cancer center’s scientific review committee and our data safety monitoring board.”

In the community setting, Braun-Inglis noted that very few APPs are enrolling their patients in trials even though they can do so for trials in the symptom management/ quality-of-life cancer care delivery space. Based on the survey findings, over 70% of APPs would like to have a larger role in clinical research (

). “I want us to really participate to the extent that our licensure, our scope, and our role within our institutions will allow,” she said.

Figure. Snapshot of APPs in Oncology Practice

Braun-Inglis also emphasized that there is no formal training available for APPs at this time, but access to initiatives could be beneficial in 4 areas: 

How to assess a patient for a trial in everyday practice•

How to become a good investigator and follow good clinical practice

How to review a study protocol for feasibility and scientific integrity

How to play a role in protocol development and leadership

This year, the Advanced Practitioner Society for Hematology and Oncology (APSHO) launched a research and quality task force to identify needs within the APP community, with a goal to develop curriculum that APPs can access. “We still see only 3% to 5% of adult oncology patients going on trials,” Braun-Inglis said. “Here we are, a group of health care providers that has grown exponentially in the last 10 years. We’re not being routinely engaged in this process. I think the interest is there; now [the question is] how do I do this at my practice?”

Zitella noted that an area of opportunity for oncology APPs is to be educated and aware of clinical trials and to be able to discuss them as a potential treatment option for patients. “There are a number of organizations trying to increase awareness and education about clinical trials for APPs, including APSHO and ACCC,” she said. “I think that if people are involved with professional organizations, go to meetings and network with other oncology APPs, and hear about what other people are doing...that makes a difference.”

APPs Can Shape the Future of Clinical Trials

Currently, APPs are not able to order drugs or treatments for Cancer Therapy Evaluation Program (CTEP)-sponsored trials or any drug that holds an investigational new drug application, all of which contribute to a substantial barrier in practice. 

In September 2020, the NCI developed a guideline that allows APPs to sign for drugs for nontreatment trials. “Even though there is that guideline that exists now, it’s still fuzzy,” Braun-Inglis explained. “You meet barrier after barrier. Our whole platform is to allow us to practice at the top of our licensure and scope within the realm of trials and not have the trial or the sponsor of the trial limit our practice. I’m hoping in the next couple of years or even a year that we’re going to see the changes come from the CTEP-sponsored trials. My real push is to make APPs leaders for other trials because we do all those things every day. There is no reason that we shouldn’t have a significant amount of involvement.” 

Zitella said there has been a significant shift in the last year because the NCI clarified some of the responsibilities of nonphysician investigators. “All cooperative groups now have nursing committees, and I think that we are going to see more progress in integrating APPs into those roles,” Zitella said. “I think the other area where we’re going to see a lot of progress is integrating the patient; this is a key element for the future of clinical trial design. Academic medical centers, professional organizations, cooperative groups, and the NCI are really trying to partner with community oncology practices to make it easier and more feasible to conduct clinical research and to have them be a part of clinical trials.” 

Kottschade noted that clinical trials in oncology are often the best option for patients for treatment, and in some cases, the only option and that APPs will affect the extent to which clinical trials are leveraged in the community setting. “The use of APPs in the community setting will expand access for patients to be enrolled on clinical trials, through increased awareness, education, and access,” she said.

Braun-Inglis added, “I would love for APPs to take a look at their practice, look at the clinical research available in their practice, and really evaluate [how they can be] practicing at the top of their scope and licensure.” 

Zitella emphasized the importance of always considering clinical trials as treatment options. “Even if you don’t work in clinical trials, being aware of them, knowing where to find them and feeling comfortable discussing them with patients, is really important because patients are relying on us for our opinion and for our knowledge,” she said.

Kurtin SE, Taher R. Clinical trial design and drug approval in oncology: a primer for the advanced practitioner in oncology. 

. 2020;11(7):736-751. doi:10.6004/jadpro.2020.11.7.7

First large-scale survey of advanced practice providers in oncology shows growing role for nurse practitioners and physician assistants. News release. American Society of Clinical Oncology. August 22, 2018. Accessed July 7, 2021. 

https://www.asco.org/about-asco/press-center/news-releases/first-large-scale-survey-advanced-practice-providers-oncology

Bruinooge SS, Pickard TA, Vogel W, et al. Understanding the role of advanced practice providers in oncology in the United States. 

. 2018;14(9):e518-e532. doi:10.1200/JOP.18.00181

Cooper RA, Henderson T, Dietrich CL. Roles of nonphysician clinicians as autonomous providers of patient care. 

. 1998;280(9):795-802. doi:10.1001/jama.280.9.795

Sarzynski E, Barry H. Current evidence and controversies: advanced practice providers in healthcare. 

Naylor MD, Kurtzman ET. The role of nurse practitioners in reinventing primary care. Health Aff (Millwood). 2010;29(5):893-899. doi:10.1377/hlthaff.2010.0440

Fairman JA, Rowe JW, Hassmiller S, Shalala DE. Broadening the scope of nursing practice. 

 2011;364(3):193-196. doi:10.1056/NEJMp1012121

Kartha A, Restuccia JD, Burgess JF Jr, et al. Nurse practitioner and physician assistant scope of practice in 118 acute care hospitals. 

 2014;9(10):615-620. doi:10.1002/jhm.2231

Braun-Inglis CM, Boehmer L, Zitella LJ, et al. Role of oncology-advanced practitioners to enhance clinical research. 

. 2020;38(suppl 29):95. doi:10.1200/JCO.2020.38.29_suppl.95 

Articles

For those in the community setting, several barriers to clinical research prevent advanced care providers and their patients from taking part in experimental  therapies.

Advanced Practice Providers Are Poised to Boost Community Involvement in Clinical Trials

Pharmacists can play a role in the drug reimbursement process for oncology products, which are among the most expensive of all pharmaceuticals. Pharmacy leaders who spoke with 

 said they can assist with revenue cycle management process, working with the billing and finance teams if any payment is denied and ensuring therapies have prior authorization from private payers.

Reimbursement for drugs has historically been determined with the average wholesale price, which was set by manufacturers. But the average annual cost of new cancer drugs continues to trend upward, although the median cost dropped by $13,000 in 2018 to $149,000, and the cost per product ranged between $90,000 and over $300,000 (

As the net cost of cancer drugs is anticipated to continue to increase, policy has been set such that costs are determined using the average selling price (ASP), which is calculated by dividing the manufacturer’s total revenue for a particular drug by the number of units sold (excluding particular sales, including those to the government).

For Medicare Part B drugs, the Centers for Medicare & Medicaid Services reimburses based on the ASP + 6% (4.3% due to sequestration),

 and there is also a difference if an infusion center is a hospital-based outpatient department. In this case, the Outpatient Prospective Payment System bundles drugs that cost less than a predetermined threshold. Private insurance generally reimburses a negotiated percentage of the charges.

“Information such as site of care and the payer mix play a particularly significant role [in determining reimbursement],” explained Scott A. Soefje, PharmD, MBA, director of Pharmacy Cancer Care Services at the Mayo Clinic in Rochester, Minnesota.

Often institutions will implement a chargemaster, which lists individual costs for each drug. The role of the pharmacy in this process varies by institution. Drug markups are determined by institutions, with a recent report of a median of 2.4 (range, 1.8-3.0) for cancer drugs.3 In this study, a markup ratio of 3.5 means that for every $100 that Medicare pays, the hospital charged $350, or $250 in excess charges. This report also found higher markups for medical oncology services were associated with for-profit status.

Institutions must determine which price to use as the baseline value for the markup among average wholesale price, ASP, wholesale acquisition cost, and actual acquisition cost. Although pharmacy operations may have input on this process, it may be determined based on what can easily be integrated with the electronic health record and billing system to generate charges.

“The final area that pharmacy can affect is the cost of the drug,” Soefje explained. “Through contracting, the department can negotiate discounted prices. If the charges are set on something other than acquisition cost, then the difference between the charge and cost widen and revenue increases. Those institutions that choose to use acquisition cost feel it is important to pass on the savings from negotiations to the customer.”

Community practices have benefited by having pharmacists on staff. They can help manage drug inventory, ensure safe prescribing practices, keep up with current guidelines, improve outcomes, educate patients, and assist the billing department to ensure reimbursement.

According to Ryan Haumschild, PharmD, MS, MBA, director of Pharmacy Services at Emory Healthcare in Atlanta, Georgia, working with payers can be difficult due to the preferred formulary and preferred products, particularly when trying to provide optimal care for patients.

“Initially, a prescriber may choose a medication that he or she feels is most appropriate for the patient, but due to payer restrictions and preferred products, oftentimes it requires a lot of additional communication and coordination to make sure that we’re dispensing the right product for the patient when they show up,” Haumschild said. “It requires a lot more coordination and operational burden, and it requires us to have multiple sites and carry multiple products based on payer preferences.”

Specifically, challenges arise with patients who have cancer because providers want to treat them as soon as possible. Delays in preauthorizations from the payer can make the process more complex in that pharmacists must ensure that the operations of switching out drugs occur safely and that the dosing and frequency are considered at the time the patient needs to be treated.

Other challenges arise after reviewing denied claims when no preauthorizations are required. Haumschild also emphasized the importance of building in feedback from highcost drugs to be sure enough information is supplied to help ensure reimbursement.

According to Haumschild, pharmacists can aid prescribers with therapy choices to ensure that drugs are FDA approved, included in the National Comprehensive Cancer Network guidelines, and will be reimbursed. Pharmacists also help with drug information in the electronic health records. Pharmacists who are having the medications compounded and dispensed must choose the correct medications, the correct National Drug Code, and ensure the charge is captured appropriately when it is administered.

According to Soefje, a drug is not likely to be reimbursed if it is not in the compendia at the required level for the use proposed. In this case, the pharmacy can help with patient assistance programs to try to obtain the drug.

“Once a denial has occurred, pharmacy can help to ensure all the appropriate coding has been done to ensure the claim is accurate,” Soefje said. “Often, a pharmacist can help clarify the coding or knows something about the patient that the coders missed that help the claim. Pharmacists are also involved when the denial is going to appeal and requires a letter of medical necessity and/or literature support.”

“I see a lot of changes coming,” Haumschild explained. “As we see less revenue coming in based on hospital-based reimbursement, we’ve got to figure out another way to still be able to provide care. With reimbursement shifts in site of care, it also takes the care away from the hospital or the clinic, which creates additional strategies on how to ensure our patients are getting the best treatment possible.” Haumschild also noted that more drugs will migrate into the ambulatory care and outpatient setting and more scrutiny over drug expenses may potentially reduce the amount of reimbursement.

According to Soefje, the biggest shift will be toward value-based payments where reimbursement will be tied to episodes of care and the outpatient focus will shift from revenue to cost. “The goal of the pharmacy will be to minimize cost while maximizing value,” Soefje explained. “The institution will receive bonus payments for high-quality care, and the focus will shift to outcomes and patient experiences. In the next 3 to 5 years, more than half of all payments will be in some form of value-based payments.”

Soefje also explained that institutions must shift to consider the total cost of care rather than individual drug costs, and the costs of drugs will be evaluated based on the associated patient outcomes. “The cheapest drug may not always be the best and we must always remember that the drug that does not work or is not taken is the most expensive drug,” Soefje said.

Haumschild suggests creating a tip sheet detailing the largest payers and their preferred oncology agents. He also explained that it is important to create a secondary process so that if the provider receives an insurance denial, there is an efficient method for swapping medication decisions and updating clinical data in real time to keep safety as a primary factor for all decisions. He also highlighted the importance of creating strategies to maintain financial sustainability.

Outpatient infusion center pharmacies must prepare for the shift from a revenue focus to a cost-outcomes focus,” Soefje noted. “We also have to think in a big picture mode, in that it might be appropriate to spend more on a drug if it prevents a hospitalization or an emergency department visit. Value will be the key. Everything that an institution does will need to be valuable to someone, and that value needs to be measured and reported.”

Haumschild also highlighted the importance of assessing outcomes. “If we are going to operate with the best care for our patients and the best outcome, we can’t just talk about the models and explain them, but we actually have to show the outcomes and show how the outcomes are better,” Haumschild explained. “And I think that’s really where the value proposition will be at the forefront of the patient and the practice.”

“It will be a difficult balance to improve throughput in the clinic, while at the same time assuring the patient feels they have received the care they want,” Soefje said. “Value cannot be reiterated enough. We have to eliminate the waste in health care and ensure that the outcomes are maximized while we reduce the total cost of care.”

“I would also say that with specialty pharmacy, you need to make sure that your health system specialty pharmacy has access to limited distribution medications because there are data out there that show that health systems and specialty pharmacies provide a higher touch of care, they provide more integrated care, and they can come up with better outcomes for those patients,” Haumschild said.

IQVIA Institute. Global oncology trends 2019: therapeutics, clinical development, and health system implications. Published May 30, 2019. Accessed April 15, 2020. Bit.ly/3ebkksE

Gordan L, Schaedig C, Weidner S. The financial impact of the sequester cut to Medicare Part B drug reimbursement in community oncology. 

. Published August 29, 2018. Accessed April 15, 2020. Bit.ly/34D8Quz

Park A, Xu T, Poku M, Taylor J, Makary MA. Variation in markups on outpatient oncology services in the United States. 

. Published February 2018. Accessed April 15, 2020. 24(2):e59-e60. Bit.ly/34FGbVB

Gatwood, J, Gatwood, K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. 

. 2017;74(19): 1549-1557. doi.org/10.2146/ajhp160475

Clinical Pharmacists in Oncology Practice. 

. 2008;4(4):172-174. doi:10.1200/JOP.0843001

Ostriker S. The growing value of a pharmacist in community oncology practice. 

Pharmacists can play a role in the drug reimbursement process for oncology products, which are among the most expensive of all pharmaceuticals. 

Pharmacy Operations Can Enhance Reimbursement Picture for Oncology Drugs

The manual labor involved in obtaining prior authorizations (PAs) is a well-recognized burden among providers. Up to 46% of PA requests are still submitted by fax, and 60% require a telephone call, according to America’s Health Insurance Plans (AHIP).1 A 2018 survey by the American Medical Association (AMA) found that doctors and their staff spend an average of 2 days a week completing PAs.2 In addition to eating up time that physicians could spend with patients, PAs also contribute to burnout.

Further, the requirements for PAs appear to be increasing. A survey by the Medical Group Management Association (MGMA), which advocates on behalf of physicians, indicated that 90% of physician respondents (N = 999) said PA requirements by payers increased in 2019. Just 1% indicated they decreased. PA requirements have steadily increased since 2016, according to respondents (FIGURE 1).3

In January, AHIP in collaboration with payers representing 60 million covered individuals launched the Fast Prior Authorization Technology Highway (Fast PATH) to improve the PA process. The system lets providers access a patient’s benefit entitlements and, if required, submit PA requests directly through the EHR. Payers in this initiative include Anthem, Blue Shield of California, Cambia’s affiliated health plans, Cigna, Florida Blue, and WellCare.1

Various software vendors are stepping into this space. Recondo said in a 2019 release that its AuthInitiate system could reduce average time spent on PA requests “from a manual 25 minutes to less than 3 minutes.”5

Although payers are often the target of contentions that they deliberately stymie the PA process to keep claims costs as low as possible, they have much to gain from participating in automated PA, according to Karina Abdallah, PharmD, clinical operations manager at Blue Cross Blue Shield of Michigan. For payers, electronic PAs reduce manual labor and enable sophisticated, real-time tracking and measurement of requests that allow not only payers but also drug manufacturers to enact rapid interventions, should inefficient or undesired trends emerge.

Abdallah, who discussed the issue at the recent Specialty Therapies and Biosimilars Congress, in Miami, Florida, said Blue Cross Blue Shield uses incentives and continuous coaching to encourage staff to promote the use of electronic PAs by providers. “High utilization of existing tools ensures that payers feel justified expanding capabilities to further automate the processes, thereby reducing provider burden,” she explained.

Individual practices are finding that among these new systems, opportunities exist to significantly cut down on the routine tasks inherent in PA and free up staff and financial resources for other activities. This is sometimes referred to as robotic process automation (RPA).

“RPA is helpful if the process is routine and repetitive,” said Alti Rahman, MHA, MBA, CSSBB, practice administrator at Oncology Consultants in Houston, Texas. “The idea is that RPA essentially takes those routine steps and performs [them] for you.”

RPA, a set of technologies and processes designed to automate otherwise manual work, has been shown to help solve the manual and disparate nature of the PA process, according to Syam Palakurthy, CEO of SamaCare, a vendor and designer of software for addressing administrative needs of practices. SamaCare, based in the San Francisco Bay Area, California, has built a system for managing and tracking PAs for specialty medications that several practices currently use.

RPA may involve automatically pulling relevant information from EHRs or tracking responses for authorization requests from payers. It enables a practice to use a single interface for all relevant payers, relying on automation to translate the practice’s input into the payer’s unique tax forms and eliminating the need to learn individual payers’ systems.

The origin of electronic PA is rooted in the increasingly omplex nature of modern practice, especially in oncology. An increased knowledge base and the development of novel therapies have contributed to improved outcomes for patients with both early- and late-stage cancer. These advances have occurred in parallel with increased costs of providing optimal oncology care.6 Many medical payers have imposed requirements for PA related to aspects of cancer care, including imaging, molecular testing, surgery, oral, infusional antineoplastic agents, and supportive care therapies. However, PAs have not only contributed to administrative burden for providers and payers but have also delayed care or caused suboptimal therapy for patients. As a result, software vendors and many on the provider and payer sides increasingly pitch RPA as a way to improve practice workflows and PA processes.

The PA process was designed to ensure that a requested therapy fits within care guidelines and the medical rationale for use provided by the clinician to the medical payer. “PA would provide certainty to providers of reimbursement, confidence to payers of medical and financial appropriateness, and assurance to patients of getting the best therapy for their circumstances,” explained Palakurthy.

“Specialty drugs, a class of drugs that are more personalized, complex to manufacture, and expensive, are especially likely to require PA,” Palakurthy said. “As the number of specialty drugs has grown by approximately 1200% since the mid-1990s, payers have ratcheted up the requirements to use them.”

For these specialty drugs, providers follow a unique process for each drug and payer. “Sometimes they fax paper documents, sometimes they enter information through idiosyncratic payer web portals, and sometimes they submit PAs via time-consuming phone calls,” Palakurthy noted.

Following the implementation of PA requirements, payer pressures, including PA and coverage denials and appeals, were reported as the top practice pressures in a 2017 American Society of Clinical Oncology survey of 7203 hematologists and oncologists. 7 Further, in the PA survey of 1000 practicing physicians conducted by the AMA, 86% of respondents reported a high or extremely high burden associated with PA in their practice. Notably, 88% of respondents reported that PA burdens have increased over the past 5 years, with practices seeing an average of 31 PA requests per physician each week (FIGURE 2).2

“The basis for what [payers] use to determine what the rules are for approval can vary payer by payer because each payer could have their own set of guidelines,” Rahman said. He believes the need to cover multiple specialties in medicine has prevented payers from devising a simplified, uniform set of oncology practice guidelines.

Other challenges for the PA process include the use of antiquated technology, such as fax, which is labor intensive. Also, payers have varying degrees of sophistication for informing practices when they have completed a PA. Practices may have to check to determine whether a PA has been read. “That disconnect leads to frustration,” Rahman said.

According to Palakurthy, providers must gather data for payers, submit the PA, and review the payer’s response to the PA request. This process becomes more complex based on the unique mechanism for each payer, which may include particular tax forms, web portals, or phone-based requests. Furthermore, a payer may change the PA process at any time. “The disparate process requires the practice to learn several dozen processes and forms for each payer, rather than becoming proficient on 1 consistent process,” Palakurthy said. “As a consequence of the manual and disparate process, delays and errors creep in that ultimately harm patient care.”

According to the AMA survey, 91% of physicians reported care delays associated with treatments requiring PA, with 28% reporting that the PA process contributed to serious adverse events, including death, hospitalization, disability or permanent bodily damage, and other life-threatening events.2 Additionally, 75% reported that issues related to the PA process led to patients abandoning the recommended treatment course, and 91% perceived an overall significant or somewhat negative impact of the PA process on patient clinical outcomes.

RPAs can help address the redundancies of the PA process and streamline a provider’s associated tasks. “RPA can facilitate that and essentially use technology to see [whether] a status has changed or not and retrieve that information for you as well,” said Rahman, who uses the SamaCare system for RPA.

“RPA can also help payers streamline internal operations,” explained Palakurthy. By allowing providers to easily send information digitally rather than through fax or phone, payers are more likely to receive PA requests in a structured form. Palakurthy also noted that the combined use of structured data and systematized protocol will enable payers to automate their PA processes.

“The SamaCare system digitizes the prior authorization process and uses RPA to streamline the time and effort required to get PA approval,” Palakurthy said. “Several practices have described SamaCare as speeding up their PA workflow by 2 to 4 times and reducing the likelihood of errors that could cause patient delays or financial losses for the practice.”

Rahman’s practice has created an automated process for 5 payers. The system automatically pulls from the EHR and facilitates the data transfer into each of the payers’ portals. “The need for visiting those portals has really completely diminished,” Rahman explained. “Of course, we have received nothing but positive feedback on being able to flatten that experience.”

Rahman cautioned that practices should ensure they understand the process before hiring a vendor to create RPA processes. Practices can evaluate many technologies on a trial basis to better understand their nature before purchasing. “When we started the process, we had some understanding of what RPA was and we started creating our own processes, so we had some idea of what we were going into,” Rahman said.

“The next few years will move us closer to an ideal where payer-practice communication facilitates patient care rather than harming it,” explained Palakurthy. He anticipates that, with time, an increasing amount of this work will be automated. “This will help push administrative burdens to having the right amount of influence on patient care: none.”

Ideally, Rahman concluded, just 1 set of rules would exist for PA, across all payers, but he doubts that will happen. “Ideally, it would be nice if all payers could operate through a singular PA clearinghouse where the rules were the same.”

To obtain PA, physicians may need to speak with payer representatives on a peer-to-peer basis to justify ordering a particular test or treatment for a patient. The peer may be a pharmacist or a physician from a different specialty who lacks expertise in oncology, which may increase the difficulty in that justification of a requested therapy.

MGMA findings also indicated that PA processes at provider practices remain largely manual: 52% are fully manual, 36% are partially electronic, and 12% are fully electronic. 4 However, software is now available to help synchronize electronic health records (EHRs) with payer portals and automate the PA process.

In January, America’s Health Insurance Plans in collaboration with payers representing 60 million covered individuals launched the Fast Prior Authorization Technology Highway to improve the prior authorization process. 

Automated Prior Authorization Catches On

The paradigm for treating patients with HER2-positive breast cancer is changing throughout the spectrum of the disease as a result of recent clinical trial findings regarding novel and established treatment regimens, according to Sara A. Hurvitz, MD. The focus on new strategies is needed because of the aggressive nature of the HER2- positive subtype; although trastuzumab (Herceptin) has substantially improved outcomes for this patient populations, approximately 25% of patients with earlystage disease will experience relapse within 10 years of a curative-intent, trastuzumab-based chemotherapy regimen.

 “For these reasons, multiple HER2-targeted therapies have been and are being developed to improve outcomes associated with this aggressive type of cancer,” Hurvitz, medical oncologist and medical director, Clinical Research Unit for the University of California, Los Angeles Jonsson Comprehensive Cancer Center, told OncLive®. “Understanding how and when to use each of these drugs is critical as we strive to optimize outcomes for our patients.”

There have been many data presented relating to neoadjuvant and adjuvant treatment for patients with HER2-positive breast cancer—–including data for trastuzumab, pertuzumab (Perjeta), neratinib (Nerlynx), and ado-trastuzumab (T-DM1; Kadcyla)–– which have contributed to practice changes (

). In an interview ahead of the 37th Annual Miami Breast Cancer Conference® (MBCC), Hurvitz previewed a few notable studies. “At the conference I will be reviewing practice-changing trial data from studies including KATHERINE, APHINITY, ExteNET, APT, and ATEMPT and will present a strategy for selection of optimal curative-intent neoadjuvant and/or adjuvant therapy for HER2-positive, early-stage disease,” Hurvitz explained.

In the phase III, open-label KATHERINE trial (NCT01772472), 1486 patients with HER2-positive, early-stage breast cancer and residual invasive disease at surgery following neoadjuvant therapy containing a taxane and trastuzumab were randomized to receive adjuvant T-DM1 or trastuzumab for 14 cycles.

 At the interim analysis, invasive disease or death was reported in 12.2% of patients receiving T-DM1 and in 22.2% of patients receiving trastuzumab. Patients in the T-DM1 group had significantly higher invasive disease-free survival (iDFS) compared with patients in the trastuzumab group (HR, 0.50; 95% CI, 0.39-0.64; 

 <.001). Distant recurrence as the first invasive disease event occurred in fewer patients receiving T-DM1 compared with trastuzumab (10.5% vs 15.9%, respectively). More adverse events (AEs) were associated with T-DM1 compared with trastuzumab; however, no new safety signals were reported.

Based on these data, the FDA approved T-DM1 for use as an adjuvant treatment for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy. The agent was approved in May 2019 under the FDA’s Real-Time Oncology Review and Assessment Aid pilot program.

 In the phase III ExteNET trial (NCT00878709), 2840 women with earlystage, HER2-positive breast cancer who completed trastuzumab-based adjuvant therapy were randomized to receive 12 months of neratinib 240 mg/day or placebo. In a 5-year analysis, patients who received neratinib had significantly fewer disease-free survival events (HR, 0.73; 95% CI, 0.57-0.92; 

 = .0083) and a higher 5-year iDFS rate (90.2% vs 87.7%) compared with those who received placebo.

 Treatment-emergent serious AEs were reported in 7% of women treated with neratinib and in 6% of women who received placebo, with no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Prophylaxis was not mandated by the study protocol.

The phase II APT trial (NCT00542451) included 410 patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes who received paclitaxel with trastuzumab for 12 weeks followed by 9 months of trastuzumab.

 The 3-year iDFS rate was 98.7%. Among 13 patients who experienced significant asymptomatic declines in ejection fraction, 11 were able to resume trastuzumab following a brief treatment interruption. In an analysis of the APT trial, the 7-year iDFS was 93%, the 7-year overall survival (OS) was 95%, and the 7-year recurrence-free interval was 97.5%.

 These data demonstrate excellent long-term outcomes with adjuvant paclitaxel and trastuzumab, along with a similar subtype distribution in small HER2-positive tumors compared with larger tumors, according to Hurvitz.

In the ATEMPT trial (NCT01853748), 497 patients with early-stage HER2-positive breast cancer were randomized to receive T-DM1 (3.6 mg/kg; 17 cycles) or 80 mg/m

 paclitaxel plus 2 mg/kg trastuzumab for 12 cycles, followed by 6 mg/kg trastuzumab every 3 weeks for 13 cycles.

 The 3-year iDFS rate was 97.7% among patients who received T-DM1 compared with 92.8% among patients who received paclitaxel plus trastuzumab.

A similar proportion of patients developed clinically relevant toxicities in both treatment groups; however, patients receiving paclitaxel plus trastuzumab reported more neuropathy (24% vs 11%), neutropenia (13% vs 3%), and infusion-related reactions (11% vs 5%), whereas patients receiving T-DM1 reported more thrombocytopenia (11% vs 1%) and elevated liver function (9% vs 4%). These results suggest that T-DM1 is an alternative treatment for select patients with early HER2-positive disease who are concerned about toxicities associated with paclitaxel/trastuzumab treatment.

Data from a multicenter, open-label, phase I/II study (NCT00398567) demonstrate encouraging tolerability and antitumor activity of neratinib plus trastuzumab in patients with pretreated, advanced HER2-positive breast cancer. Patients with locally advanced or metastatic HER2-positive breast cancer who received ≥1 prior trastuzumab-based regimens demonstrated a 16-week progression-free survival (PFS) rate of 44.8%, with a median PFS of 15.9 weeks among 28 evaluable patients treated with the combination of neratinib and trastuzumab.8 The most common AE was diarrhea, and no clinically significant toxicity was reported.

 The fact that tucatinib met 3 major end points—PFS, PFS in the population with brain metastases, and OS&mdash;at its first reporting, with a good safety profile, is incredible news for patients,” Hurvitz noted.

In the phase II DESTINY-Breast01 study (NCT03248492), 184 patients with HER2-positive metastatic breast cancer who received prior T-DM1 were treated with [fam-] trastuzumab deruxtecan-nxki (Enhertu).

 Overall, 112 patients responded to therapy. The median duration of PFS was 16.5 months (95% CI, 12.7 months to not reached). The most frequently reported grade ≥3 AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). These data demonstrate durable antitumor activity in pretreated patients with HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan.

“The waterfall plot showing responses from [trastuzumab deruxtecan] was remarkable,” Hurvitz said. “Almost everyone had disease shrinkage with this novel antibody-drug conjugate. This is very exciting for heavily pretreated disease. The FDA’s accelerated approval of [trastuzumab deruxtecan] in December [2019] based on a phase II trial is just 1 example of the rapid availability of new drugs with promising results.”

The confirmatory phase III randomized trial for DESTINY-Breast01, DESTINYBreast02 (NCT03523585), is currently enrolling patients. They will be randomized to either trastuzumab deruxtecan or physician’s choice of capecitabine plus either trastuzumab or lapatinib (Tykerb).

In the phase III SOPHIA trial (NCT02492711), 536 patients with HER2-positive metastatic breast cancer that progressed following 2 or more lines of anti-HER2 therapy were randomized to chemotherapy combined with either margetuximab or trastuzumab.

 Results from an interim analysis after 270 patient deaths demonstrated a median PFS of 5.7 months with margetuximab treatment compared with 4.4 months with trastuzumab treatment. The overall response rate (ORR) was significantly higher among patients treated with margetuximab compared with those treated with trastuzumab (25.2% vs 13.7%; 

 = .0006). The clinical benefit rate was also significantly higher among those treated with margetuximab (48.1% vs 35.6%; 

 = .0025). AEs were similar overall; however, infusion-related reactions were more frequent among patients treated with margetuximab (13.3% vs 3.4%). Data from the SOPHIA trial are the first to suggest superior PFS with a novel antibody compared with trastuzumab, Hurvitz said.

Finally, in the phase II monarcHER trial (NCT02675231), patients with advanced hormone receptor—positive, HER2-positive breast cancer were randomized to receive trastuzumab plus chemotherapy or abemaciclib (Verzenio), fulvestrant (Faslodex), and trastuzumab.

 The median PFS was higher among patients who received abemaciclib, fulvestrant, and trastuzumab compared with those who received the combination of trastuzumab and chemotherapy (8.32 vs 5.69 months).

“I was also very happy to see the results from the phase II, randomized monarcHER trial, showing an improved ORR and PFS in patients with HR-positive/HER2-positive metastatic breast cancer treated with abemaciclib, fulvestrant, and trastuzumab compared with those treated with chemotherapy plus trastuzumab,” Hurvitz explained. “These data support preclinical data suggesting that CDK4/6 [inhibitors] should have activity in [patients with] HR-positive/ HER2-positive breast cancer.”

Treatment decision making has become more complex with the development of novel therapies for patients with HER2-positive breast cancer; however, researchers are investigating methods to guide therapy selection in this patient population. Results from a pooled analysis of over 5000 patients with breast cancer demonstrated that the measurement of residual cancer burden (RCB) index was associated with tightly associated with both event-free survival (EFS) and distant recurrence-free survival (DRFS) and was prognostic for all breast cancer phenotypes (

). “We found that these results were consistently generalizable and could help determine the most appropriate treatment plans for patients with all breast cancer subtypes,” noted W. Fraser Symmans, MD, professor and director of research operations in the Department of Pathology at The University of Texas MD Anderson Cancer Center, in an interview.

Investigators assessed RCB through a number of factors including dimensions of the primary tumor-bed area, the percentage of invasive versus in situ cancer, the number of lymph nodes involved, and the size of the largest metastasis. These data were entered into a calculator developed by MD Anderson following a pathologic examination after neoadjuvant treatment and calibrated to an estimate of the patients’ risk for recurrence over time. The RCB index was classified as RCB-I (minimal burden), RCB-II (moderate burden), or RCB-III (extensive burden).

Among patients with HR-positive/HER2-positive disease, 38% were classified as achieving a pathological complete response (pCR), with 20% classified as RCB-I, 33% as RCB-II, and 8% as RCB-III. After 10 years of follow-up, 9% of patients who had a pCR had experienced a recurrence or had died, compared with 17% of patients classified as RCB-I, 36% of RCB-II, and 55% of RCB-III.

Among patients with HR-negative/HER2- positive disease, 69% were classified as achieving a pCR, with 11% classified as RCB-I, 16% as RCB-II, and 4% as RCB-III. After 10 years of follow-up, 7% of patients who had a pCR had experienced a recurrence or had died, compared with 15% of patients classified as RCB-I, 37% of RCB-II, and 40% of RCB-III.

“This pooled analysis confirms and expands upon prior findings that RCB index can predict risk of breast cancer recurrence,” Symmans said. “This assessment of prognostic risk can be used to accurately determine disease progression and inform treatment choice for breast cancer patients inclusive of all subtypes.”

“In the early disease setting, I am interested in trials like ATEMPT and APT that are pursuing less toxic approaches for select patients deemed to be at low risk, but hope to see long-term follow-up to ensure that a de-escalation approach is safe,” Hurvitz said. She also explained that, in the metastatic setting, she is interested in data from HER2CLIMB related to the effects of tucatinib in patients with active central nervous system metastases. “I am looking forward to seeing how many patients have responses in the brain with this drug,” she said. “This will potentially be practice changing for the management of this challenging but alltoo- common clinical scenario.”

“Multiple therapeutic options are now available for both early- and late-stage HER2- positive disease,” Hurvitz concluded. “The field is rapidly evolving given the number of agents that can target the HER2 driver. Now, more than ever, it is critical for clinicians to keep up-to-date with emerging trial results, as many studies are yielding practice-changing data. In the next year, it would not be surprising if we see the approval of 1, if not 2, additional agents for this disease.”

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. 

. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.

von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. 

. 2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.

Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase III trial. 

. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.

Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. 

. 2015;372(2):134-141. doi: 10.1056/NEJMoa1406281.

Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. 

. 2019;37(22):1868-1875. doi: 10.1200/JCO.19.00066.

Tolaney SM, Hu J, Dang C, et al. TBCRC 033: a randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-05.

FDA approves Genentech’s Kadcyla for adjuvant treatment of people with HER2-Positive early breast cancer with residual invasive disease after neoadjuvant treatment [press release]. South San Francisco: Genentech; May 3, 2019. bit.ly/2UYWOVN. Accessed February 20, 2020.

Blackwell KL, Zaman K, Qin S, et al; 202 Study Group. Neratinib in combination with trastuzumab for the treatment of patients with advanced HER2-positive breast cancer: a phase I/II study. 

. 2019;19(2):97-104.e4. doi: 10.1016/j.clbc.2018.12.011.

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019]. 

. 2020;382(7):597-609. doi: 10.1056/NEJMoa1914609.

Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators.

Trastuzumab deruxtecan in previously treated HER2-positive breast cancer [published online December 11, 2019]. 

. 2020;382(7):610-621. doi: 10.1056/NEJMoa1914510.

Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-02.

Tolaney SM, Wardley AM, Zambelli S, et al. MonarcHER: A randomized phase 2 study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of care chemotherapy in women with HR+, HER2+ advanced breast cancer. Presented at: 2019 European Society Medical Oncology Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA23.

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01. abstractsonline.com/pp8/#!/7946/presentation/1923. Accessed February 17, 2020.

In the HER2CLIMB trial (NCT02614794), 612 patients with HER2-positive metastatic breast cancer, with or without brain metastases, who previously received trastuzumab, pertuzumab, and T-DM1, were randomized to tucatinib or placebo combined with trastuzumab and capecitabine.

 At 1 year, PFS was significantly higher in patients receiving tucatinib compared with those receiving placebo (33.1% vs 12.3%; HR, 0.54; 95% CI, 0.42-0.71; 

 <.001). Similar results were seen among patients with brain metastases (24.9% vs 0%). At 2 years, OS was significantly higher in the tucatinib group compared with the placebo group (44.9% vs 26.6%). Diarrhea and elevated aminotransferase levels were more frequent among patients receiving the tucatinib combination. These data demonstrate improved survival outcomes with the addition of tucatinib to trastuzumab and capecitabine among heavily pretreated patients with HER2- positive metastatic breast cancer, including patients with brain metastases.

In the APHINITY trial (NCT01358877), 4805 patients with node-positive or high-risk node-negative, HER2- positive operable breast cancer were randomized to receive pertuzumab or placebo plus standard adjuvant chemotherapy and 1 year of trastuzumab.

 Disease recurrence was reported in significantly fewer patients who received pertuzumab compared with those who received placebo (HR, 0.81; 95% CI, 0.55-1.00; 

 = .045). The 3-year iDFS rate was 94.1% in the pertuzumab group compared with 93.2% in the placebo group. Among those with node-positive disease, the 3-year iDFS rate was significantly higher compared with that of the placebo group (HR, 0.77; 95% CI, 0.62-0.96; 

 = .02). Grade ≥3 diarrhea was reported almost exclusively during chemotherapy; however, it was more frequent among those treated with pertuzumab compared with those treated with placebo (9.8% vs 3.7%).

The paradigm for treating patients with HER2-positive breast cancer is changing throughout the spectrum of the disease as a result of recent clinical trial findings regarding novel and established treatment regimens, according to Sara A. Hurvitz, MD

Navigating the Changing Landscape in HER2-Positive Breast Cancer

In breast cancer, genetic signatures have been used to predict response to chemotherapy and hormone treatment, as well as risk of metastasis. Their utility as predictors of response to radiation has been unclear. However, recent studies have demonstrated that somatic mutations of 

 denote greater response to radiation therapy and that gene patterns may help predict the timing of recurrence following radiation.

“There are several commercially available platforms that are used in different clinical settings to predict recurrence after treatment,” said Sumanta K. Pal, MD, an expert commentator for the American Society of Clinical Oncology (ASCO). “One prominent example is the Oncotype DX recurrence score test, which helps guide the decision for adjuvant chemotherapy in breast cancer. The role of this platform is well established through randomized trials. Similarly, there are several molecular tools in prostate cancer [Decipher and Oncotype DX AR-V7 Nucleus Detect] that aid in predicting outcome following definitive treatment. However, clinicians are somewhat divided on the utility of these tools.”

Studies are underway to identify specific gene mutations associated with the response to radiation therapy. Previous findings suggest that mutations of genes involved in DNA repair, such as 

, may contribute to chemotherapy resistance and a poor prognosis, but may also denote sensitivity to radiation therapy. In a study presented at ASCO’s Breakthrough: A Global Summit for Oncology Innovators, held in October 2019 in Bangkok, investigators sought to determine whether tumors with 

 mutations were more susceptible to radiotherapy.

mutations confer “exceptional responses to radiation therapy,” offering potential for therapeutic value.

Because radiation works by damaging DNA, a DNA damage repair gene, such as 

, that malfunctions may confer sensitivity of a tumor to radiation treatment. “In this context, our study showed that the 

Recent studies have demonstrated that somatic mutations of ATM denote greater response to radiation therapy and that gene patterns may help predict the timing of recurrence following radiation. 

Erin M. Burns, PhD, MSPH

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