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Clinical Utility of Emerging Molecular Diagnostics in Breast Cancer

Marie-Kristin von Wahlde, MD; Tomoko Kurita, MD; Tara Sanft, MD; Erin Hofstatter, MD; Lajos Pusztai, MD, DPhil
Published: Wednesday, Mar 09, 2016

Marie-Kristin von Wahlde, MD

Marie-Kristin von Wahlde, MD


Molecular diagnostic tests are increasingly used in the clinic to tailor therapy to the molecular characteristics of a cancer. In early stage estrogen receptor (ER)-positive cancer, the 21-gene recurrence score assay, as well as other gene expression signature-based tests are routinely used to assist in identifying patients for adjuvant chemotherapy. A new generation of tests has also been developed for ER-positive cancers to estimate the risk of late recurrence and benefit from extended adjuvant endocrine therapy and therefore identify patients who require 10 years of endocrine therapy. Among triple-negative breast cancers (TNBC), there is increasing evidence that patients with germline BRCA mutant cancers are highly sensitive to platinum drugs, and inclusion of this agent with an anthracycline- and taxane-based regimen might improve their outcome. Other proposed “BRCA-ness” markers are also being tested in the clinic. Extensive immune cell infiltra-tion (lymphocyte predominant breast cancer) that can be detected by counting tumor-infiltrating lymphocytes or measuring immune-specific gene expressions is an increasingly recognized favorable prognostic marker that also predicts greater chemotherapy sensitivity in TNBC and high-risk, ER-positive cancers. The clinical utility of immune markers is yet to be defined, but their importance will likely grow as immunotherapies are entering the clinic. In HER2-positive cancer, several markers demonstrated statistically significant associations with response to HER2-targeted therapies, but their predictive values to select one therapy over another or to omit HER2-targeted therapies are modest and have little clinical utility. Molec-ular target profiling of metastatic cancers is increasingly performed to determine clinical trial eligibility for targeted drugs and to identify potentially druggable alterations. Anecdotal examples demonstrate benefit from off-label use of targeted therapies in some patients with a matching molecular abnormality, but the clinical utility of this strategy is still under study in several ongoing clinical trials.


Clinically useful molecular diagnostic tests enable more selective use of therapies and therefore could lead to more cost-effective care and spare patients from potential side effects of ineffective therapies. In breast cancer, several diagnostic tests have emerged that meet criteria for clinical use, and many other tests are currently being investigated in clinical studies to assess their clinical value.

Estrogen Receptor-Positive Cancer

For estrogen receptor (ER)-positive early-stage breast cancer, molecular tests are available to assist in answering two important questions: who benefits from adjuvant chemotherapy, and who remains at risk for late recurrence despite 5-years of adjuvant endocrine therapy and therefore may require extended adjuvant endocrine therapy? The OncotypeDX 21-gene recurrence score, the Prosigna PAM50-risk-of-recurrence score, the MammaPrint gene signature, and the Breast Cancer Index each represent standardized, commercially available mRNA expression-based molecular diagnostic tests in the US that can be used to identify patients who are the most likely to benefit from adjuvant chemotherapy through measuring the expression of estrogen signaling and proliferation-related genes. The predictive utility of these tests is derived from their ability to simultaneously identify cancers that are high-risk for recurrence and also have sensitivity to chemotherapy.1 The predictive value of each of these tests is supported by substantial evidence, and all major breast cancer practice guidelines support the use of multigene diagnostic assays, in conjunction with other clinical pathological parameters, to help select patients for adjuvant chemotherapy. However, when more than one assay is applied to the same cancer, they can yield discordant prediction results as often as 20 to 30% of the time, particularly for borderline risk categories.2,3

The sample-level concordance between test results is modest because they rely on different genes, algorithms, and platforms and currently it remains unknown how to handle discordant results.3 Several studies have demonstrated the cost effectiveness of these assays but the impact of test results on adjuvant chemotherapy use depends on the patient population that is being tested.4-6 In clinically high-risk patient populations (e.g. node-positive or >1 cm) chemotherapy use tends to decrease, while in the low-risk populations (e.g. node-negative and <1 cm) chemotherapy use increases among patients who had testing compared to those who were not tested.7

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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