Best of ASCO Charlotte 2026: Early-Stage Breast Cancer Updates
Faculty: Elyse E. Lower, MD
Professor Emerita, University of Cincinnati
The Bottom Line
At the 2026 Best of ASCO Charlotte conference presented by Total Health, Dr Elyse Lower focused her presentation on two studies that challenge long-standing treatment paradigms in early-stage breast cancer through carefully designed non-inferiority trials. Rather than asking whether a new treatment is superior to the current standard, both studies asked whether clinicians can safely do less, or de-escalate therapy – that is, avoiding unnecessary chemotherapy or additional surgery without compromising patient outcomes. She emphasized that, as treatment options continue to expand, such non-inferiority trials are becoming increasingly important because they allow clinicians to reduce toxicity while maintaining efficacy.
The first study, OPTIMA, demonstrated that the Prosigna® (PAM50) genomic assay may identify selected patients with clinically high-risk, hormone receptor (HR)-positive/HER2-negative early breast cancer who derive little benefit from adjuvant chemotherapy, including patients with four to nine positive lymph nodes - a population for whom prospective genomic data had been lacking. The second study, SENOMAC, showed that omitting complete axillary lymph node dissection in patients with one or two sentinel lymph node macrometastases does not compromise survival while substantially reducing long-term arm morbidity. Although Dr Lower believes additional follow-up is needed before OPTIMA is fully incorporated into practice, she described SENOMAC as immediately practice changing.
Background: Non-Inferiority as a Trial Endpoint
Dr Lower began by stepping away from the trial data to explain why both featured studies were designed as non-inferiority trials. Historically, oncology studies have sought to demonstrate that one treatment is superior to another. Today, however, effective therapies already exist for many cancers, making placebo-controlled studies impractical or even unethical. As a result, investigators are increasingly asking whether a newer strategy can provide equivalent clinical outcomes while reducing toxicity, treatment burden, or cost. She explained that a properly conducted non-inferiority trial must define in advance the maximum acceptable difference between treatments and demonstrate that the newer, less burdensome approach remains within that predefined margin. Importantly, success in these trials is not measured solely by survival outcomes; improvements in quality of life, convenience, and treatment-related toxicity are equally important considerations. Dr Lower described both OPTIMA and SENOMAC as excellent examples of this study design, noting that each met the key methodological criteria required for a valid and informative non-inferiority trial.
Trial Design: Two Key Questions in De-Escalation
OPTIMA
The OPTIMA trial was an international phase III randomized study evaluating whether the 50-gene Prosigna genomic assay could be used to guide adjuvant chemotherapy decisions in patients with clinically high-risk HR-positive/HER2-negative early breast cancer. Eligible patients were at least 40 years of age and had one to nine positive lymph nodes or stage IIIA disease. Patients randomized to the experimental arm underwent Prosigna testing; those with low risk of recurrence (ROR) scores (≤60) received endocrine therapy alone, while those with higher scores received chemotherapy followed by endocrine therapy. All premenopausal women in OPTIMA were required to receive ovarian function suppression (OFS), an important aspect of the study that Dr Lower repeatedly highlighted during her discussion. More than 4,100 patients were enrolled, including nearly one in five patients with four to nine positive lymph nodes, and Dr Lower noted this was a population that has historically been underrepresented in genomic assay trials. She also noted that most clinicians in the United States are familiar with the Oncotype DX genomic assay because it has helped guide chemotherapy decisions in patients with up to three positive lymph nodes. Evidence has remained limited, however, for patients with heavier nodal involvement or larger tumors, and Dr Lower summarized the central hypothesis of OPTIMA with the phrase: "Biology is trumping anatomy here."
SENOMAC
The second study which Dr Lower reviewed, SENOMAC, addressed a surgical question that has remained controversial despite earlier de-escalation studies. Patients with clinically node-negative breast cancer and one or two sentinel lymph node macrometastases were randomized following surgery to either complete axillary lymph node dissection (ALND) or no additional axillary surgery. Unlike many earlier trials, Dr Lower noted that SENOMAC enrolled patients undergoing both breast-conserving surgery and mastectomy, included patients with T1 through T3 tumors, and incorporated the use of more contemporary radiation therapy approaches. Nearly 2,800 patients from five European countries participated, with patient-reported outcomes collected prospectively through five years of follow-up.
Main Trial Results
OPTIMA
Approximately two-thirds of patients enrolled in OPTIMA had low Prosigna recurrence scores, allowing investigators to compare outcomes between patients treated with endocrine therapy alone and those receiving standard chemotherapy followed by endocrine therapy. Across the study population, invasive breast cancer-free survival met the predefined criteria for non-inferiority. Similar findings were observed for distant recurrence-free survival, and no meaningful differences emerged across key subgroups, including menopausal status, tumor size, stage IIIA disease, or nodal burden, even among patients with four to nine positive lymph nodes. Although Kaplan-Meier curves consistently showed a small numerical advantage favoring chemotherapy, the absolute differences were modest, amounting to roughly one to two percentage points at five years. Dr Lower emphasized the practical significance of these findings, explaining that chemotherapy prevented, at most, two recurrences for every 100 patients treated. From her perspective, this represents an important opportunity to spare carefully selected patients the toxicity of chemotherapy without sacrificing meaningful clinical benefit - as she remarked, "I think we all agree that getting rid of chemotherapy is a good thing."
Despite the encouraging results, however, Dr Lower urged some caution, as median follow-up was approximately four years, with nearly two-thirds of patients who had not yet reached five years of follow-up. In addition, the study largely enrolled White patients and began before adjuvant CDK4/6 inhibitors became part of routine management for many patients with node-positive disease. She also pointed out that Prosigna has been used primarily in Europe, and as such, the test remains unfamiliar to many U.S. oncologists - an observation illustrated by the fact that only one audience member reported having previously ordered the assay. Nevertheless, Dr Lower believes the trial fills an important evidence gap for patients with four to nine positive lymph nodes, stage IIIA disease, and premenopausal women over age 40 who are receiving ovarian suppression.
SENOMAC
Dr Lower then reviewed findings from SENOMAC, which she considered even more immediately relevant to everyday practice. She noted that overall survival at five years was virtually identical whether patients underwent completion ALND or no additional axillary surgery, confirming the study's primary non-inferiority endpoint. Rates of local recurrence, regional recurrence, distant recurrence, and breast cancer-specific survival were similarly comparable between treatment groups. Importantly, these outcomes were achieved despite the omission of a procedure that has historically been considered standard for patients with sentinel lymph node macrometastases.
The greatest differences in the trial emerged in patient-reported outcomes, in that those patients who avoided complete ALND experienced significantly fewer arm symptoms, better physical function, and improved quality of life throughout follow-up. Severe or very severe arm-related complications occurred in only about 4% of patients who omitted ALND compared with approximately 12% of those who underwent the procedure. Because more than one-third of study participants underwent mastectomy, a group largely absent from earlier axillary de-escalation trials, Dr Lower felt the results were highly applicable to modern clinical practice.
Study Implications: Adverse Events and Toxicities
For OPTIMA, the principal benefit was not a reduction in a specific adverse event per se but rather the opportunity to avoid chemotherapy altogether in patients unlikely to derive meaningful benefit. Dr Lower stressed that reducing unnecessary treatment is itself an important clinical outcome, provided survival is maintained.
In SENOMAC, however, the reduction in treatment-related morbidity was substantial. Patients who avoided complete axillary dissection reported consistently better arm function and fewer long-term symptoms, a result translating into meaningful improvements in daily activities and overall quality of life. As such the findings reinforce a central premise of non-inferiority trials - that reducing treatment intensity can provide important patient benefits without compromising cancer outcomes.
Conclusions and Faculty Insights
Dr Lower concluded that both OPTIMA and SENOMAC represent outstanding examples of well-conducted non-inferiority trials and reflect a broader movement toward treatment de-escalation in breast cancer. While she believes OPTIMA requires longer follow-up before widespread adoption, she views the study as an important step toward more biologically driven treatment decisions. While she acknowledged that many U.S. clinicians have limited experience with Prosigna she nonetheless predicts that this is likely to change as additional evidence emerges, particularly for patients with heavier nodal involvement. "We're going to become much more familiar [with Prosigna], especially in this four to nine [lymph node] group" she said. By comparison, Dr Lower’s assessment of SENOMAC was unequivocal. After reviewing the survival, recurrence, and quality-of-life data, she suggested that omission of completion axillary lymph node dissection should become the new standard of care for appropriately selected patients with one or two sentinel lymph node macrometastases. As she told the audience, "I think it is, in my mind, definitely practice changing."
Speaker Disclosure Information: Dr Lower reported no relevant disclosures for this presentation.