PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy (ET) represents the standard first-line treatment for patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2-negative) advanced breast cancer (ABC). However, there is no definitive consensus on the preferred second-line treatment option. The PALMIRA trial investigated whether palbociclib rechallenge with an alternative ET would improve the antitumor activity in patients progressing after a first-line palbociclib-containing regimen. METHODS: This international, randomized, open-label, phase II study enrolled 198 patients with hormone receptor–positive/HER2-negative ABC with disease progression after first-line palbociclib plus ET (aromatase inhibitor or fulvestrant). Patients were eligible if they showed clinical benefit to the previous regimen (response or stable disease ≥24 weeks) or had progressed on a palbociclib-based therapy in the adjuvant setting. Patients were randomly assigned (2:1 ratio) to either palbociclib rechallenge plus second-line ET (fulvestrant or letrozole) or second-line ET alone. Stratification factors were previous ET and visceral involvement. The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: Between April 2019 and October 2022, 136 and 62 patients were randomly assigned to palbociclib plus ET or ET alone, respectively. Median investigator-assessed PFS was 4.9 months (95% CI, 3.6 to 6.1) with palbociclib plus ET versus 3.6 months (95% CI, 2.5 to 4.2) with ET alone (hazard ratio, 0.84 [95% CI, 0.66 to 1.07]; P = .149). Grade ≥3 treatment-emergent adverse events were higher with palbociclib plus ET (47.4% v 10.0%), without new safety signals. CONCLUSION: Palbociclib rechallenge plus an alternative ET did not significantly improve PFS compared with ET alone in patients with hormone receptor–positive/HER2-negative ABC progressing on a first-line palbociclib-based ET regimen.

HER2DX is a clinically available genomic assay that provides prognostic (relapse risk score), predictive [pathological complete response (pCR) likelihood score], and ERBB2 expression data in stage I-III human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). This real-world study evaluated its clinical impact. This prospective study enrolled newly diagnosed patients with stage I-III HER2-positive BC across 12 hospitals in Spain (November 2021-September 2024). Thirty-four oncologists ordered HER2DX and completed questionnaires before and after receiving results to assess treatment changes (primary objective). Secondary objectives included evaluating the HER2DX pCR likelihood score association with pCR, test turnaround time, changes in physician confidence regarding treatment decisions, and cost-effectiveness. Among 297 recruited patients, 48.1% (95% confidence interval 42.5% to 53.7%) experienced treatment adjustments after HER2DX. Within these cases, 73.5% involved reduced treatment intensity, 24.5% involved increased treatment intensity, and the remaining cases (2.0%) involved mixed adjustments. Of the cases with reduced treatment intensity, 56.2% had a reduction in chemotherapy intensity, 26.7% had a reduction in anti-HER2 therapy, and 17.1% in both. Among the 182 patients with available pathological data at surgery, the pCR likelihood score was a significant predictor of pCR (P < 0.001). In 69 patients with pCR-high disease, less intensive treatment achieved similar pCR rates compared with multi-agent chemotherapy (81.5% versus 69.0%; odds ratio = 1.97, P = 0.256). Physician confidence improved (P < 0.001) and the estimated total cost savings, including direct drug costs, vein access devices, and HER2DX costs, amounted to €98 031. HER2DX impacts clinical management in stage I-III HER2-positive BC by supporting treatment adjustments, enhancing physician confidence, maintaining pCR rates, and reducing health care costs.

In triple-negative (TNBC) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer patients, neoadjuvant systemic therapy is the standard recommendation for tumors larger than 2 cm. Monitoring the response to primary systemic therapy allows for the assessment of treatment effects, the need for breast-conserving surgery (BCS), and the achievement of pathological complete responses (pCRs). In estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer, the benefit of neoadjuvant strategies is controversial, as they have shown lower tumor downstaging and pCR rates compared to other breast cancers. In recent decades, several gene expression assays have been developed to tailor adjuvant treatments in ER+/HER2- early breast cancer (EBC) to identify the patients that will benefit the most from adjuvant chemotherapy (CT) and those at low risk who could be spared from undergoing CT. It is still a challenge to identify patients who will benefit from neoadjuvant systemic treatment (CT or endocrine therapy (ET)). Here, we review the published data on the most common gene expression signatures (MammaPrint (MP), BluePrint (BP), Oncotype Dx, PAM50, the Breast Cancer Index (BCI), and EndoPredict (EP)) and their ability to predict the response to neoadjuvant treatment, as well as the possibility of using them on core needle biopsies. Additionally, we review the changes in the gene expression signatures after neoadjuvant treatment, and the ongoing clinical trials related to the utility of gene expression signatures in the neoadjuvant setting.

Background: The 21-gene Oncotype DX Breast Recurrence Score^® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2− early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score^® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. Methods: Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1–2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians’ confidence levels in their final recommendations. Results: A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians’ confidence in their final recommendations increased in 34% of cases. Conclusions: Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.