Gene-Expression Assays in Early-Stage Breast Cancer: Who Should Order Them and When?

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Cesar A. Santa-Maria, MD, MSCI

Cesar A. Santa-Maria, MD, MSCI

Ashley Cimino-Mathews, MD

Ashley Cimino-Mathews, MD

Antonio C. Wolff, MD, FACP, FASCO

Antonio C. Wolff, MD, FACP, FASCO

A deeper understanding of biology has allowed significant advances in the treatment of breast cancer. In the early-stage setting, standard pathology measures can help identify which subset of patients with hormone receptor–positive breast cancers are more likely to experience benefit from adjuvant chemotherapy, and major efforts have focused on improving the accuracy of predictive biomarker testing. In recent years, several molecular assays assessing tumor biology became commercially available in the United States and Europe, including Prosigna, MammaPrint, and Oncotype DX. Most have been clinically validated for their prognostic utility, and some predict outcome in the presence or absence of adjuvant chemotherapy.1-3

This study demonstrates the value of carefully examining clinical workflow and identifying potential barriers to the timely delivery of medical care.
— Cesar A. Santa-Maria, MD, MSCI, Ashley Cimino-Mathews, MD, and Antonio C. Wolff, MD, FACP, FASCO

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While these assays examine various genes related to breast cancer, they are largely associated with measures of proliferation.4 Ideally, their incremental utility occurs when they provide information that does not simply replicate that of high-quality pathologic assessment. Timing is also a factor, as a decision to order a molecular assay may delay final clinical decision-making; however, automatically ordering such tests for every single newly diagnosed breast cancer case may not always be helpful or required. 

When recommended, adjuvant chemotherapy should preferably begin no later than 12 weeks after surgery, as this was the usual timeline allowed in clinical trials, and indirect evidence suggests that delays may affect outcomes.5-8 Usually, adjuvant therapy starts as soon as the patient recovers from surgery, but this can be affected by how multidisciplinary breast cancer care is organized at local institutions. Hence, there is a critical need to ensure that patients be seen in a timely fashion by the various disciplines involved in their care and that all needed information be available to minimize decision delays. 

Surgeon-Initiated Oncotype DX Ordering

Recently, as reviewed in this issue of The ASCO Post, investigators from Dana-Farber Cancer Institute published their experience in this regard in the Journal of Oncology Practice.9 The authors had observed that the delay in ordering Oncotype DX may lengthen the time between surgery and the initiation of adjuvant chemotherapy (an average of 43.7 days at their institution). Therefore, they evaluated the impact of implementing surgeon-initiated ordering of Oncotype Dx in the immediate postoperative period, which would occur once pathology was available and based on criteria developed by the multidisciplinary team. Those criteria included age 65 or younger; estrogen receptor–positive disease; and T1c, N0 (grade 2 or 3), or T2, N0 (grade 1 or 2), or T1–2, N1 (grade 1 or 2) disease. 

While it is possible to craft parameters for ordering molecular tests, we should not see this as the only intervention that would minimize delays in clinical decisions.
— Cesar A. Santa-Maria, MD, MSCI, Ashley Cimino-Mathews, MD, and Antonio C. Wolff, MD, FACP, FASCO

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From January 2014 until November 2016, 720 consecutive patients who underwent Oncotype DX testing were examined. The authors observed that surgeon-initiated ordering, vs a control cohort of usual care, led to significant reductions in the time from surgery to -Oncotype DX ordering, from surgery to the receipt of results, and from surgery to the initiation of adjuvant chemotherapy of 7.3 days, 6.3 days, and 6.4 days, respectively. 

This study demonstrates the value of carefully examining clinical workflow and identifying potential barriers to the timely delivery of medical care. It also shows that standardized quality improvement initiatives with multidisciplinary input can improve patient care workflow, speed transition times across disciplines, and reduce variability in test-ordering patterns. 

Study Limitations 

The authors acknowledge potential limitations in their analyses, such as incomplete pathology report information, time to start of other treatment such as endocrine therapy or radiation therapy, information on the impact on patient/provider satisfaction, whether cost savings were observed, and clinical outcomes. Furthermore, their manuscript does not report certain key descriptions of the two cohorts, including different types and numbers of breast and axillary surgeries or patients who had postoperative complications. Another important parameter not provided is the median time to first medical oncology visit, which is especially important, as this is where final decisions are usually made about whether to pursue adjuvant chemotherapy. 

While a 1-week delay in adjuvant chemotherapy is unlikely to have adverse outcomes in terms of recurrence risk or overall survival, there is no doubt that, for patients, each additional day in deciding to pursue adjuvant chemotherapy or not can be stressful and provoke anxiety. However, one must remember that the assessment as to whether adjuvant chemotherapy could potentially further improve clinical outcomes of disease-free and overall survival can, in many cases, be made based on information already available from a standard pathologic assessment. 

Relationship Between Oncotype DX and Standard Pathology

Recently, a research team led by investigators at Johns Hopkins reported on the ability to estimate with greater than 95% confidence the likelihood that an observed molecular test result with Oncotype DX would be above or below a certain threshold. In this case, a recurrence score of 25 was chosen based on the design of ongoing clinical trials such as TAILORx ( identifier NCT00310180) and RxPONDER (NCT01272037), which are prospectively evaluating the clinical utility of this assay.10 The model was developed using histopathologic markers that are often available and that were locally tested, such as estrogen receptor, progesterone receptor, Ki67, HER2, and Nottingham grade (ie, Elston-Ellis modification of the Scarff-Bloom-Richardson grading system). 

These investigators found that their model performed with the expected degree of certainty in over half of patients who had routine pathologic assessment and Oncotype DX testing across five institutions. They then tested and validated an online interactive nomogram aptly named the Breast Cancer Recurrence Score Estimator ( Their data show that there are circumstances in which information offered by molecular tests may be readily available on routine pathologic assessment.10 Hence, efforts should focus on determining when ordering these assays will maximize the chances that the test result complements, and not simply replicates, information already available. Data comparing clinical outcomes when decisions integrate molecular and pathologic data vs when they do not are also lacking. 

Optimizing Multidisciplinary Practice

The treatment of breast cancer requires a multidisciplinary approach. Thus, timely and organized workflow is crucial for an optimal patient experience. If it takes a patient several weeks after surgery to secure a medical oncology appointment, a delay in decisions regarding whether and when to start adjuvant therapy becomes inevitable. Even in settings equipped with a multidisciplinary clinic, where patients see medical, surgical, and radiation oncology practitioners at the time of their initial encounter with the breast cancer team, the initial diagnostic workup and pathology diagnosis often may be insufficient to allow final decisions regarding adjuvant systemic therapy. 

Thus, one simple approach might be to ensure that, as soon as a surgical date is scheduled, a medical oncology appointment (initial or follow-up) is scheduled for immediately after the surgical postoperative visit. This scheduling-based approach would reduce delays in ordering additional tumor testing, such as molecular testing, and would allow the medical oncologist to integrate standardized decision-making tools already available in the pathology report, along with allowing a better assessment of patient preferences regarding the potential use of adjuvant chemotherapy. 

Efforts like those pursued by Losk et al, which are designed to identify pathology parameters to trigger an earlier decision to order the test once the pathology report becomes available, can certainly reduce the test-ordering variability often seen in large multidisciplinary practices. At the same time, there is value in allowing those ultimately involved in the final decision to pursue chemotherapy or not (eg, the patient and the medical oncologist) an opportunity to decide if the test information may influence clinical decision-making. 

Undoubtedly, any delay in the start of adjuvant therapy is a source of major stress for patients and their support network. The ordering of any test, however, should be done when it is expected that the test result may further inform clinical decision-making. While it is possible to craft parameters for ordering molecular tests, we should not see this as the only intervention that would minimize delays in clinical decisions. In some cases, a “low-tech” intervention, like centralized and timely appointment scheduling, could circumvent delays as patients navigate across the various disciplines involved in the care of those with newly diagnosed breast cancer. ■

DISCLOSURE: Drs. Santa-Maria, Cimino-Mathews, and Wolff reported no conflicts of interest.

Dr. Santa-Maria, MD, MSCI, is Assistant Professor of Oncology, Dr. Cimino-Mathews is Associate Professor of Pathology, and Dr. Wolff is Professor of Oncology, Breast and Ovarian Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.


1. Sparano JA, Gray RJ, Makower DF, et al: Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 373:2005-2014, 2015.

2. Cardoso F, van’t Veer LJ, Bogaerts J, et al: 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 375:717-729, 2016.

3. Parker JS, Mullins M, Cheang MC, et al: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160-1167, 2009.

4. Sahebjam S, Aloyz R, Pilavdzic D, et al: Ki 67 is a major, but not the sole determinant of Oncotype Dx recurrence score. Br J Cancer 105:1342-1345, 2011.

5. Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, et al: Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol 2:322-329, 2016.

6. Gagliato Dde M, Gonzalez-Angulo AM, Lei X, et al: Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 32:735-744, 2014.

7. Lohrisch C, Paltiel C, Gelmon K, et al: Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 24:4888-4894, 2006.

8. Yu KD, Huang S, Zhang JX, et al: Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: A systematic review and meta-analysis. BMC Cancer 13:240, 2013.

9. Losk K, Freedman RA, Lin NU, et al: Implementation of surgeon-initiated gene expression profile testing (Oncotype DX) among patients with early-stage breast cancer to reduce delays in chemotherapy initiation. J Oncol Pract 13:e815-e820, 2017.

10. Kim HS, Umbricht CB, Illei PB, et al: Optimizing the use of gene expression profiling in early-stage breast cancer. J Clin Oncol 34:4390-4397, 2016.

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