The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2− breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study’s inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2− eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2− breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2− eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment.

Detection of minimal residual disease (MRD) in early breast cancer (EBC) after curative-intent treatment may identify patients at risk for recurrence. Most circulating tumor DNA (ctDNA)-based MRD assays require knowledge of genomic alterations from tumor tissue. However, tissue availability may be limited in some patients. Here, we evaluated sensitivity and specificity for recurrence detection, using a plasma-only ctDNA MRD assay. For this pilot study, 47 plasma samples from 38 EBC patients were collected at 12 or 36 months post-diagnosis or at clinical recurrence. ctDNA presence was determined by a custom bioinformatics classifier that identifies tumor-derived somatic variants and methylation profiles specific to individual cancer types using a 5-Mb next-generation sequencing panel. ctDNA was detected at or before distant recurrence in 11/14 (79%) patients [sensitivity was 85% (11/13) among samples collected within 2 years from recurrence]. Lead time was evaluable in 4/6 (67%) samples collected before distant recurrence with detectable ctDNA and ranged from 3.4 to 18.5 months. ctDNA was not detected in samples from patients without recurrence (n = 13). This study demonstrates the feasibility of MRD detection in EBC using a plasma-only multiomic ctDNA-based approach. Larger studies are ongoing to further validate the clinical performance of the assay and demonstrate its applications.

Background: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2−) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2− breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. Methods: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women’s Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. Results: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2− tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2− breast cancer (TNBC). Of 2039 HER2− breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2− breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2− patients and 87 of 141 (61.7%) patients with TNBC). Conclusion: Approximately one in ten patients with HR+/HER2−, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

Background: Current aftercare in breast cancer survivors aims to detect local recurrences or contralateral disease, while the detection of distant metastases has not been a central focus due to a lack of evidence supporting an effect on overall survival. However, the data underpinning these guidelines are mainly from trials of the 1980s/1990s and have not been updated to reflect the significant advancements in diagnostic and therapeutic options that have emerged over the past 40 years. In this trial, the aim is to test whether a liquid biopsy-based detection of (oligo-) metastatic disease at an early pre-symptomatic stage followed by timely treatment can impact overall survival compared to current standard aftercare. Methods: In this partially double-blinded superiority study, intensified liquid biopsy-guided surveillance will be assessed versus standard surveillance in medium-to-high-risk early breast cancer patients. Intensive surveillance comprises 3-monthly tests of circulating free tumor DNA (ctDNA), circulating tumor cells (CTC) and serum tumor markers CEA, CA 27.29 and CA125. Upon positivity of biomarker and/or symptoms, staging examinations are initiated. In total, 3500 patients will be randomized in a 1:1 ratio after completion of primary antineoplastic therapy. Co-primary endpoints are overall survival (OS) and the overall lead time effect. The trial will be accompanied by an extensive translational research program. Discussion: A risk-based aftercare and regular screening for asymptomatic metastatic disease with molecular markers in the absence of any radiological findings can potentially revolutionize current follow-up care of breast cancer survivors and enable potential treatment even before patients suffer from symptomatic, incurable disease.

Background: Current evidence on circulating tumor DNA (ctDNA) in the adjuvant setting of early breast cancer (eBC) confirms its high prognostic value. CtDNA-positive patients without radiographic signs of relapse show reduced disease-free and overall survival. Secondary adjuvant treatment intervention studies represent a new appealing therapeutic option. Methods: We present SURVIVE HERoes , a phase III randomized clinical trial of the potent antibody-drug conjugate trastuzumab deruxtecan versus standard of care (SoC) in patients with HER2 positive or HER2 low eBC and molecular residual or recurrent disease (ctDNA positive, cM0) after primary therapy. The primary endpoint is the ctDNA clearance rate after 12 months of therapeutic intervention. A total of 180 study participants will be enrolled and randomized in a 2:1 ratio to receive trastuzumab deruxtecan or SoC therapy. The trial is accompanied by an extensive translational research project. Discussion: Treating ctDNA positive patients without radiographic signs of recurrence is a novel approach. If SURVIVE HERoes and similar studies targeting MRD will be positive, this may lead the way to a new molecular understanding of breast cancer stages and individualized therapy and may open a new therapeutic window for cure.

Current aftercare after early breast cancer overlooks recent evidence on circulating free tumor DNA (ctDNA). In this case report, we present a patient with low-risk hormone-receptor-positive breast cancer. ctDNA was first detected using a tumor-informed approach 12 months after the initial diagnosis and remained positive throughout adjuvant therapy with letrozole, while routine staging examinations showed no signs of relapse. Clinical relapse was ultimately identified nearly six years after the initial diagnosis, resulting in a lead time of four years and nine months. Current studies on ctDNA in the adjuvant setting have been conducted in high-risk cohorts and have shown a median molecular lead time of 8.9–12.4 months. Our study supports the need for large randomized clinical trials involving low-risk breast cancer patients to drive changes in clinical practice.