Recent American Society of Clinical Oncology practice guidelines recommended the use of MGAs to assist with decision-making for patients with HR+/HER2-early breast cancer (BC). Among the most widely used MGA is Oncotype DX, a 21-gene test; however, many gray areas exist in the application of this test. A narrative review was published to help address six areas of uncertainties.
One limitation is that Oncotype DX does not consider clinicopathological (CP) factors, such as patient age, tumor size, nuclear grading, and HR levels, when generating a genomic score. Its recurrence score (RS) is based solely on the molecular characteristics of the tumor. While clinical risk features alone are prognostic, they do not predict whether chemotherapy (CT) will be beneficial. Integrating CP factors into RS may lead to more accurate prognoses, which will help guide the choice of optimal adjuvant BC therapy. Benefit from CT may be more pronounced in patients with an intermediate RS who are at higher clinical risk. Additional tools include the RS-pathology and clinical model, which predicts prognosis, and the RSClin tool, which has both prognostic and predictive properties that can assist in adjuvant treatment decision-making.
Another evolving area is whether women with HR+/HER2- early BC and lymph node–positive disease (LN+D; 1-3 nodes) should undergo MGA to help minimize their risk of recurrence. Recent data indicated that genomic testing could identify women who are most likely to derive benefit from CT. It appears that postmenopausal women who have HR+/HER2- early BC with one to three LN+D can forego CT, but CT appears to be beneficial for premenopausal women as these patients experience greater invasive disease-free survival. It is unclear if the benefit in this population is due to eliminating micrometastatic disease or amenorrhea secondary to CT. There is evidence supporting improvement in overall survival and disease-free survival among premenopausal women who experience CT-induced amenorrhea for at least 6 months postadjuvant CT. Others have suggested that whereas CT is most beneficial in higher RS, endocrine therapy (ET) and ovarian function suppression (OFS) may be useful in younger women with RS <25. To add to the controversy, ASCO 2022 recommendations advised against MGA testing of premenopausal HR+/HER2- with LN+D, but the European Society of Medical Oncology advocates for testing along with consideration of other CP factors to help support decisions regarding systemic treatment in intermediate-risk patients.
Another area that lacks clarity is whether patients undergoing neoadjuvant chemotherapy (NAC) or neoadjuvant endocrine therapy (NET) should have MGA testing performed, as there are a lack of data predicting the efficacy of such testing. Since pathological complete response rate (pCR) is significantly higher in patients with a high RS compared with either low or intermediate RS, RS may predict patients who may benefit from NAC. Studies employing Oncotype DX have found a lower clinical response rate in patients with high genomic risk (i.e., RS >30) and a higher rate of partial response in patients with low RS (RS <11) and intermediate RS (RS = 25-30). NET was not found to be successful in achieving pCR in patients with lower RS and in those with intermediate risk; however, NAC was beneficial resulting in a rate of pCR of 22% in those with RS >25.
The value of MGA testing in patients with histologies other than ductal carcinoma is unclear. Invasive lobular carcinoma, which accounts for 10% to 15% of all BC diagnoses, differs from ductal carcinoma in receptor status expression and biological aspects, leaving many questions about the utility of RS as prognostic or predictive indicators in this type of BC. Mucinous BC is associated with low-to-intermediate RS, whereas pleomorphic and anaplastic variants are associated with intermediate-to-high RS. International guidelines on BC do not distinguish between different BC histologies when discussing MGA testing.
Another area of unchartered territory is the use of MGA in male BC patients. Men were excluded from the developmental and validatory regulatory studies for Oncotype DX, although approximately 90% of male BC patients typically have HR+/HER2- BC. While male BC patients are more likely to have either high RS (RS >31) or low RS (RS <10), there are differences in the frequency of P13kCA and TP53 mutations and a higher rate of DNA repair-related gene mutations in men. The use of traditional female RS-cutoffs in identifying differences in prognoses has been questioned. The International Male BC Program was developed to address some of these concerns.
Lag time between ordering MGA testing and receiving test results may adversely affect disease progression if it results in a delay in care. It is important to find ways to increase access and timeliness of MGA testing.
As part of the interdisciplinary team involved in shared decision-making, pharmacists should be aware of the limitations of MGA testing as patients may seek their advice in understanding and interpreting MGA testing.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published April 14, 2023