Methods to accurately predict which patients are the most likely to benefit from therapy can be elusive, according to Joyce O’Shaughnessy, MD. However, updated findings have indicated that the MammaPrint and BluePrint genomic tests could offer a predictive testing approach to elucidate which patients with hormone receptor (HR)–positive, HER2-negative early-stage breast cancer should receive adjuvant and/or neoadju- vant chemotherapy.
MammaPrint is a 70-gene assay that analyzes the most important genes associated with breast cancer recurrence.1 The MammaPrint index classifies patients as being at high risk 2 (H2; range, –1.000 to –0.570), high risk 1 (H1; range, –0.569-0.000), low risk (range, 0.001-0.355), or ultralow risk (range, 0.356-1.000) for disease recurrence.1 BluePrint is an 80-gene test that classifies patients into luminal (further strati- fied using MammaPrint into luminal A-type [low risk] and luminal B-type [high risk]), HER2, or basal subtypes, providing insights into their long-term prognosis and potential response to systemic treatment.2
“In patients with HR-positive, HER2-negative early breast cancer, the first question is, ‘Who needs chemotherapy at all?’” O’Shaughnessy said in an interview with OncologyLive. “[Most] patients will receive endocrine therapy, and if they have high enough risk disease, they will receive a CDK4/6 inhibitor. Patients with a low 21-gene recurrence score don’t benefit from chemotherapy. We know that the MammaPrint [test] is prognostic due to data from the [phase 3] MINDACT trial [NCT00433589], but we did not [previously] have data [that] indicated that a high-risk MammaPrint score predicts bene- fit from chemotherapy or that a low-risk score predicts a lack of benefit.”
O’Shaughnessy is the Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center and the director of the Breast Cancer Research Program at Texas Oncology, US Oncology in Dallas, Texas.
MammaPrint and BluePrint Show Predictive Value
To further understand the predictive value of the tests on patient outcomes, investigators initiated the prospective, observational FLEX regis-
try study (NCT03053193).3 FLEX enrolled adult patients with stage I to III breast cancer who were eligible to receive chemotherapy and endo- crine therapy and MammaPrint, with or without BluePrint testing, in any clinical setting. The study excluded patients with metastatic, recur- rent, or stage 0 disease.
During the 2024 San Antonio Breast Cancer Symposium (SABCS), O’Shaughnessy presented data from an analysis of FLEX that demonstrated that MammaPrint and BluePrint were able to predict sensitivity to neoadjuvant chemotherapy in patients with HR-positive, HER2-negative early breast cancer.
Patients with H2 luminal and basal disease (n = 159) achieved a patholog- ical response rate of 32.7%, with a pathological complete response (pCR) rate of 28.3%. Those with H2 luminal B-type (n = 70) or H2 basal (n = 83) disease experienced pathological response rates of 21.4% and 43.4%, respectively, with respective pCR rates of 15.7% and 39.8%. Comparatively, patients with low-risk luminal A-type disease (n = 44) experienced a patho- logical response rate of 4.5%, and those with H1 luminal B-type disease (n = 242) experienced a pathological response rate of 9.5%, with a pCR rate of 7.4%.
Data from a multivariate analysis also revealed that a MammaPrint H2 classi- fication was significantly associated with a pathological response compared with H1 status (OR, 3.33; 95% CI, 1.51-7.61; P = .003).4
Additional data from FLEX also presented during SABCS showed that patients with a higher-risk MammaPrint score who received adjuvant chemotherapy plus endocrine therapy (n = 501) had a significantly lower risk of 5-year distant recurrence or breast cancer–specific death (hereafter, DRFI) compared with those who received endocrine therapy alone (n = 501). Patients with an ultralow MammaPrint score who received endocrine therapy experienced a 1.0% (95% CI, 0.6%-2.2%) average 5-year DRFI risk vs 0.4% (95% CI, 0.1%-1.0%) among those who received chemotherapy plus endocrine therapy. Among patients with a low score, these respective rates were 3.2% (95% CI, 2.2%-4.5%) and 1.5% (95% CI, 1.0%-2.1%).5
Notably, patients in the H1 group who received endocrine therapy alone experienced an average 5-year DRFI risk of 10.0% (95% CI, 5.6%-14.6%) compared with 4.4% (95% CI, 2.6%-6.4%) among patients who received endocrine therapy plus chemotherapy, for a risk difference of 5.6% (95% CI, 3.0%-8.2%). In the H2 risk group, these rates were 19.1% (95% CI, 14.8%-24.8%) vs 8.2% (95% CI, 6.5%-10.6%), respectively, representing a risk difference of 10.9% (95% CI, 8.3%-14.2%).5
“These are the first data using MammaPrint showing that the higher the risk [score], the greater the benefit from chemotherapy,” O’Shaughnessy noted. “We’ve been giving chemotherapy to those women anyway because we know they have a poor prognosis, but this is the first time we’ve seen level 1, prospective, predictive data. The caveat here is that this is not a randomized trial. This [study] has a large database of real-world evidence, but the deci- sion to give chemotherapy or not is made by the physician and patient.”
Findings from FLEX have also shown the capability of MammaPrint and BluePrint to help inform the need for the addition of an anth- racycline to chemotherapy.
During the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, O’Shaughnessy presented data from FLEX that demonstrated that patients with H1 luminal disease who received an anthracy- cline plus a taxane (n = 184) achieved a 3-year relapse-free survival (RFS) rate of 95.3% (95% CI, 91.8%-98.8%) compared with 97.1% (95%, 95.1%- 99.2%) among those who received a taxane plus cyclophosphamide (n = 346). However, patients with luminal H2 tumors who received an anth- racycline plus a taxane (n = 44) experienced a 3-year RFS rate of 97.7% (95% CI, 93.4%-100%) vs 86.4% (95% CI, 74.2%-100.0%) among those who received a taxane plus cyclophos- phamide (n = 40).6
“Both of these tests are endorsed by National Comprehensive Cancer Network and ASCO guidelines, so I don’t believe there are any barriers [to access],” O’Shaughnessy said.
“In FLEX, MammaPrint and BluePrint are also being evaluated in [patients with] HER2-positive and triple-negative disease. There could poten- tially be some limitations on reimbursement there because it is a research trial. However, if we look at [data from] MINDACT, there were patients with triple-negative breast cancer who didn’t benefit from chemotherapy if they had a low-risk MammaPrint score. If they had a high-risk MammaPrint score, they had a worse prognosis and did benefit from chemotherapy.
In general, in the HR-positive, HER2-negative context, there are not any barriers to ordering [these tests], getting the results in a timely fash- ion, or to reimbursement.”
Breast Cancer Experts Gather at SOBO to Discuss the Latest Data
During the upcoming 23rd Annual School of Breast Oncology® (SOBO), which is hosted by Physicians’ Education Resource®, LLC (PER®), expert investigators in the field of breast cancer will gather to further discuss how molecular and genomic testing can be used to optimally select treatment approaches for individ-ual patients. O’Shaughnessy is set to serve as the chair of the event, which will also feature sessions on present and emerging imaging modalities, best practices for the locoregional management of patients with breast cancer, and the latest clinical trial data that could shape future therapeutic approaches. The program will be held from November 6 to 8, 2025, in Atlanta, Georgia.
“SOBO will be a 3-day deep dive [that will cover] new data based around case discussions [that aim to determine] how we apply these new data to practice,” O’Shaughnessy said. “I always thoroughly enjoy the data presentations but am also [looking forward to] the spirited inter- actions that occur during a moderated case and panel discussion between the reconstruc- tive surgeons, the plastic surgeons, and the radiation oncologists.”