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The age cap for reflex recurrence score (RS) testing should be changed for patients with early-stage, ER-positive breast cancer, based on how clinicians actually use the test and the benefit to patients, said authors of a study in .

Harold Burstein, MD, PhD, of Dana-Farber Cancer Institute/Harvard Medical School in Boston, and colleagues explained that the age cap of 65 for reflex testing was set because of Medicare reimbursement constraints rather than for clinical reasons. However, doctors can still order RS testing on an ad-hoc basis, regardless of the patient's age, and many of them do.

For the study, the team reviewed patterns of RS testing at Dana-Farber from 2019 through 2021. A total of 1,687 patients received OncotypeDX RS testing during that time. Two drivers of testing outside predefined criteria were found: the age limit and the prognostic pathological features of tumors. Together, these accounted for more than three quarters of all ad-hoc tests (469 of 600 patients), the investigators reported.

Furthermore, the study found that physicians recommended chemotherapy at the same rate in all patients regardless of age. This suggested that the clinical value of RS testing is the same in all patients fit to receive chemotherapy, Burstein and co-authors said.

"On the basis of this internal review, we have broadened the criteria for RS testing to include older patients and selected patients with pT1b G2-3 and pT1c G1 tumors. We also believe that changing reimbursement policies for RS testing in patients older than 65 years would mitigate some of the disparities in RS testing and yield a timely delivery of curative treatments," the researchers concluded.

In the following interview, co-author Dario Trapani, MD, now of the European Institute of Oncology and the University of Milan, elaborated on additional aspects of this topic.

What is the rationale for the age cap of 65 on reflex RS testing?

Trapani: There is no true clinical rationale, but some norms still split the patient population in two: older versus younger patients. In the clinical practice, and based on the international medical guidelines, such a difference in the population does not really exist. It is not true that people turning 65 will experience some sudden change in their health condition, and not true that clinically we split people below vs above 65.

The historical 65 threshold to define "old" adults is more appropriate for epidemiological studies, and to understand at population level, if health outcomes may vary in aging populations. In fact, thresholds of 65, 70, and 75 have been variously used in population studies to track the health trajectories and estimate the burden of "premature" mortality for certain diseases.

However, at the patient level, we consider how people feel, function, and act; we account for the biological age – that is, a description of the person's capacity to adapt to stressors, and to be emotionally and functionally resilient in adverse health conditions and when receiving specific treatments. We make treatment decisions based on this idea of "function" and not of "age," of "biological" rather than "chronological" age.

In practice, we use clinical evaluation, including oncogeriatric scales of assessment, to make a judgment on how "fit" patients are, and what is the estimated capacity to tolerate certain therapies. In addition to identifying the fittest to give the strongest therapy, we also make an estimate of competitive conditions that can impact someone's health.

This is a daily life risk estimation: if someone has multiple comorbidities, and is diagnosed with cancer, we need to consider the several factors that affect health outcomes, and understand how providing a treatment for one condition will affect the other conditions. It is a delicate balance.

In oncology, we need to understand if patients are frail and to what extent they will be able to tolerate standard treatments. Presently, in breast oncology, there are few examples of treatments intended "for older patients." If a patient is fit for a therapy, this is commonly the same therapy that anyone else would receive, with few exceptions.

This is an important point, because few treatments have been shown to portend some benefit when de-intensified in the elder population because of age alone. More commonly, de-intensified, non-standard treatments are suboptimal when adjusted just because someone is older than 65.

OncotypeDX in breast cancer is used to inform the decision to add adjuvant standard chemotherapy -- that is, the one having showed to improve patient outcomes -- in the setting of hormone receptor-positive and HER2-negative early breast cancer. It is clear that if someone is deemed, at any age, not fit to receive a chemotherapy, such a test should not be used to make clinical decisions.

This means the age cap at 65 is not reasonable, and there is no rationale to make such an age-based division. The only threshold that applies at 65 is patients will be covered under Medicare health insurance.

You noted that another challenge to RS testing in older patients is the 14-day rule. Can you please explain that?

Trapani: This is something that has to do with CMS, and only for laboratory tests ordered during inpatient stay of patients. This is called the Medicare date of service "14-day rule" for billing requirements of diagnostic tests ordered for Medicare patients. If a test is ordered within 2 weeks from the patient discharge, laboratories will bill the hospital for Medicare patients, and the test will not be provided under Medicare coverage.

This is very serious: false claims allegations and instrumental delays in ordering the tests (e.g., Medicare holds and cancellation of the orders less than 14 days from discharge) are seriously punished by U.S. law. Some exceptions exist for certain pathology tests that may be required to refine diagnosis and treatment decision for some tumor types -- for example, to portray comprehensively the molecular biology of lung cancer after the diagnosis or the surgical interventions.

Yet, this does not apply to OncotypeDX. The 14-day rule can be challenging in some cases for patients receiving inpatient surgical operations. Commonly, breast surgery can be performed in a 1-day outpatient service, but some patients still will need to stay in the hospital for more than 1 day. For these patients, there is an optimal temporal window between surgery and start of the therapy, and it has been shown that the longer we start "adjuvant" treatments beyond such a temporal window, the lesser is the efficacy, with an impact on patient outcomes.

This is the reason we implemented (as described in the paper) a surgeon-triggered system to order OncotypeDX, to optimize the process and achieve a fully informed clinical decision in the shortest time. However, this is not a practice common in all institutions, and for some patients, it might result in additional financial toxicity or unexpected health payments.

What do international guidelines, such as those from the International Society of Geriatric Oncology (SIOG), say about treatment restrictions based on chronological age alone?

Trapani: We mapped this information in and realized that most of the guidelines, primarily SIOG, do not recommend an age threshold. Chronological age alone is not a clinically useful or validated concept to trigger differential treatment approaches. More than 60% of the overall incident cancer cases are in patients 65 or older, meaning that much of our clinical practice is for "older" adults.

Similar rates are reported for breast cancer, which is the most commonly diagnosed cancer in the world. Multidimensional, person-centric, function and resilience-oriented evaluations are important in the treatment decision-making -- not chronological age.

What do you think it will take to convince CMS to change the age cap on reimbursement?

Trapani: I believe it shouldn't take too much. Medicare included an exception to the 14-day rule for certain genomic tests in oncology. It is important to highlight the implications for patients, and frame policies for reimbursement based on the patient's journey.

In this case, flexibility in the reimbursement should be applied, especially in those centers where 14 days may not be enough to get the necessary pathology information to understand if a test like OncotypeDX is appropriate. In fact, OncotypeDX is triggered only for specific subtypes of breast cancer, and indicated only for defined stages of disease.

What ongoing research are you doing in this area?

Trapani: The institution where we did this research, the Dana Farber in Boston, has a dedicated, terrific group working specifically on the design and delivery of person-centric, evidence-informed, and comprehensive oncogeriatric care. The research group is committed and passionate about the design of the future in this field, providing evidence on the best use of treatments across the spectrum of people age 65 and older.

Specifically, continuous efforts are underway to understand the value and estimate the benefit of new treatments in the adjuvant setting of breast cancer, as informed by tools like OncotypeDX, including in the fittest patients and for frailer populations, to result in risk-adapted innovative concepts of therapies.

Dr. Burstein and Dr. Rachel Freedman -- who is leading the oncogeriatric group -- have recently completed a , among many ongoing, oriented in this direction. They designed a study trying to enhance tolerability and quality of life while delivering non-inferior outcomes in older women with breast cancer.

In addition, Dr. Burstein has led the development of the International St. Gallen consensus, published as a , including important perspectives in the management of early breast cancer in older women.

In my own capacity, now that I work in Italy, I collaborate with the national and EU regulatory agencies, providing all the efforts to ensure equal access to best cancer care to all people, regardless of their age. With my group in Milan, at the European Institute of Oncology, for example, we supported the development of the national and regional policies for appropriateness and reimbursement of genomic tests in patients with cancer, and worked in the direction of refining person-centric precision medicine pathways, based on people's health status, not age; age is not a criterion to access these services under the national health policies of reimbursement. No current policy caps the indication or reimbursement to specific tests when clinically appropriate.

As such, I work to maintain the current status of universal access, with no additional financial burden for those individuals exposed to potential vulnerabilities, which can happen in some elder patients, by advising decision-makers and strongly advocating for inclusive health policies and evidence-informed recommendations.

Read the study here.