ASCO recently released two new clinical practice guidelines on biomarkers and their role in guiding adjuvant systemic treatment decisions in women with early-stage invasive breast cancer and systemic therapy decisions in women with metastatic breast cancer. In both cases, these guidelines are evidence based with an overt emphasis on clinical utility, defined as improvement in patient outcomes with doing the test compared to not doing the test.1
Metastatic Breast Cancer
Evidence-based biomarker test guidelines are nothing new for ASCO—the organization has been publishing these since the mid-1990s. However, efforts to identify clinical utility have become increasingly sophisticated. The field is moving quickly, and both expert panels that developed the guidelines have worked to provide practicing oncologists insight into “the appropriate use of results from assays of breast tumor biomarkers to guide or influence decisions on systemic therapy.”1
Dr. Catherine Hall Van Poznak
When making decisions about systemic therapy for women with metastatic breast cancer, clinicians are advised to use only established biomarker tests. The tissue-based (as opposed to circulating) biomarkers that have established clinical utility are estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Appropriate analyses of these tests have been addressed extensively in prior collaborations between ASCO and the College of American Pathologists.2,3
“We are recommending only the use of these three biomarkers that we’ve had for many years,” Dr. Van Poznak said. “The other tests that we assessed did not have clinical utility to show that care using this marker actually results in an improvement.” She added that other tests may have analytic validity, and with additional research may show clinical utility.
A thorough evaluation of randomized clinical trials found “insufficient data” to recommend use of circulating carcinoembryonic antigen (CEA) and assays for the MUC1 protein (cancer antigen 15-3 [CA 15-3] and cancer antigen 27-29 [CA 27-29]) alone for monitoring response to treatment.
Dr. Daniel F. Hayes
The other biomarkers “haven’t been tested in the fashion to show clinical utility, except for CTCs,” Dr. Van Poznak said. “Although number of CTCs is prognostic, the clinical utility to guide therapy decisions wasn’t there.”
Clinical utility of a biomarker is extremely important to demonstrate if treatment decisions are going to be based on biomarkers. ER, PR, and HER2 clearly demonstrated clinical utility, but the guideline also notes treatments should be based on clinical judgment and consideration of patient preferences. Biomarkers in development “need to be validated, and that takes well constructed studies and time,” Dr. Van Poznak said.
Early-Stage Invasive Breast Cancer
The number of recognized biomarkers is rising and was a main driving point for ASCO’s development of the guideline for adjuvant systemic therapy in early-stage invasive breast cancer.
After evaluating 11 biomarkers for guiding decisions on the need for adjuvant systemic therapy, in addition to ER, PR, and HER2, the panel found clinical utility for Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and uPA/PAI-1 in specific subgroups of patients with breast cancer. However, “no biomarker except for ER, PR, and HER2 was found to guide choices of specific treatment regimens.”4
Dr. Lyndsay N. Harris
“The Guideline Panel was excited to see new biomarker tests that have clinical utility in node- negative, ER-positive early-stage breast cancer,” Dr. Hayes said. “However, we have raised caution against ordering tests that may be marketed but have not been shown with high levels of evidence to have clinical utility. A bad tumor marker is as bad as a bad drug, and we believe we’ve provided good guidance to clinicians as to which tests might be used and which are not ready for clinical applicability.”
Whereas the Guideline Panel has enthusiastically endorsed several new tests for patients with ER-/PR-positive, HER2-negative, and node-negative breast cancer, they remained cautious about recommending any prognostic signature test for patients with node-positive, ER-/PR-positive, HER2-negative disease to guide decisions for adjuvant systemic chemotherapy. Although there are encouraging data to suggest such tests might be useful to identify those patients who have such a good prognosis that they could forego adjuvant chemotherapy, the Panel did not feel that the data were sufficiently strong to support such a recommendation. Prospective randomized trials are ongoing to address this issue.
Dr. Harris said that clinicians need to continue discussions with patients to develop individualized treatment plans.
“Our recommendations aren’t the only piece that goes into patient care,” she said.
“Several of the remaining biomarker tests showed analytical validity but have not been used long enough to determine if they have clinical utility.”
“The time has come to take biomarkers more seriously as a science because the strengths of the recommendations are going to be based on the strength of the scientific literature,” Dr. Van Poznak said. “For our biomarker recommendations to be solid, our clinical trials need to really integrate and embrace biomarkers as something to test.”
Dr. Hayes further noted that “we need to focus on the analytical validity and clinical utility of a tumor biomarker test before we use it to direct patient care, just as we focus on both how a drug is manufactured and prepared for administration, as well as whether the clinical trial data support its efficacy and toxicity. Caveat emptor is not a good way to practice medicine.”