Impact of Imaging-Guided Localization on Performance of Tailored Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer: Prospective Cohort Study Within TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

BACKGROUND: Tailored axillary surgery (TAS) is a novel surgical concept for clinical node-positive breast cancer. It consists of the removal of the sentinel lymph nodes (LNs), as well as palpably suspicious nodes. The TAS technique can be utilized in both the upfront and neoadjuvant chemotherapy (NACT) setting. This study assessed whether/how imaging-guided localization (IGL) influenced TAS. PATIENTS AND METHODS: This was a prospective observational cohort study preplanned in the randomized phase-III OPBC-03/TAXIS trial. IGL was performed at the surgeon's discretion for targeted removal of LNs during TAS. Immediate back-up axillary lymph node dissection (ALND) followed TAS according to TAXIS randomization. RESULTS: Five-hundred patients were included from 44 breast centers in six countries, 151 (30.2%) of whom underwent NACT. IGL was performed in 84.4% of all patients, with significant variation by country (77.6-100%, p < 0.001). No difference in the median number of removed (5 vs. 4, p = 0.3) and positive (2 vs. 2, p = 0.6) LNs by use of IGL was noted. The number of LNs removed during TAS with IGL remained stable over time (p = 0.8), but decreased significantly without IGL, from six (IQR 4-6) in 2019 to four (IQR 3-4) in 2022 (p = 0.015). An ALND was performed in 249 patients, removing another 12 (IQR 9-17) LNs, in which a median number of 1 (IQR 0-4) was positive. There was no significant difference in residual nodal disease after TAS with or without IGL (68.0% vs. 57.6%, p = 0.2). CONCLUSIONS: IGL did not significantly change either the performance of TAS or the volume of residual nodal tumor burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03513614.

ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features.

Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (ERBB2 or HER2 un-amplified) and CDH1 mutations. Rare variants include ERBB2-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2-amplified ILBC and compared these characteristics with ERBB2-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2-amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2-unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2-amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.

Prognostic impact of histological subtyping in triple-negative breast cancer.

The impact of special histological types (ST) in triple-negative breast cancer (TNBC) and its association with overall outcome has gained increasing relevance as survival has been linked to specific histological TNBC subtypes. We evaluated the clinicopathological and survival data of 598 patients with 613 TNBCs, including 464 TNBCs of no special type (NST) and 149 TNBCs ST (low-grade, n = 12, 8.1%; high-grade, n = 112, 75.2%; apocrine and androgen receptor-positive [APO AR], n = 25, 16.8%). Patients with low-grade TNBC ST and TNBC ST APO AR were significantly older (P < 0.001) and had a lower Ki67 index (P < 0.001) than those with TNBC NST. Patients with high-grade TNBC ST were significantly older (P = 0.006) and had poorer pathological responses to neoadjuvant chemotherapy (NAC) (P < 0.001) than those with TNBC NST. Significant survival differences were observed between low-grade TNBC ST, TNBC ST APO AR, high-grade TNBC ST, and TNBC NST in the entire study group (DFS, P = 0.002; DDFS, P = 0.001) and in the non-NAC subgroup (OS, P = 0.034; DFS, P = 0.001; DDFS, P < 0.001). Patients with low-grade TNBC ST had the best survival outcomes. Patients with high-grade TNBC ST showed significantly worse outcomes than those with TNBC NST (entire study group: OS, P = 0.049; DFS, P < 0.001; DDFS, P = 0.001; non-NAC subgroup: OS, P = 0.014; DFS, P < 0.001; DDFS, P < 0.001). We conclude that prognostic stratification of TNBC ST is ultimately important for optimizing the therapeutic management of patients with these rare tumor entities.

Long-Term Follow-Up of High-Risk Breast Lesions at Vacuum-Assisted Biopsy without Subsequent Surgical Resection.

Introduction: B3-lesions of the breast are a heterogeneous group of neoplasms, associated with a higher risk of breast cancer. Recent studies show a low upgrade rate into malignancy after subsequent open surgical excision (OE) of most B3-lesions when proven by vacuum-assisted biopsy (VAB). However, there is a lack of long-term follow-up data after VAB of high-risk lesions. The primary aim of this study was to demonstrate whether follow-up of B3 lesions is a beneficial and reliable alternative to OE in terms of long-term outcome. The secondary aim was to identify patient and lesion characteristics of B3 lesions for which OE is still necessary. Methods: This retrospective multicenter study was conducted at 8 Swiss breast centers between 2010 and 2019. A total of 278 women (mean age: 53.5 ± 10.7 years) with 286 B3-lesions who had observation only and who had at least 24 months of follow-up were included. Any event during follow-up (ductal carcinoma in situ [DCIS], invasive cancer, new B3-lesion) was systematically recorded. Data from women who had an event during follow-up were compared with those who did not. The results for the different B3 lesions were analyzed using the t test and Fisher's exact test. A p value of <0.05 was considered statistically significant. Results: The median follow-up interval was 59 months (range: 24-143 months) with 52% (148/286) having a follow-up of more than 5 years. During follow-up, in 42 women, 44 suspicious lesions occurred, with 36.4% (16/44) being invasive cancer and 6.8% (3/44) being DCIS. Thus, 6.6% (19/286) of all women developed malignancy during follow-up after a median follow-up interval of 6.5 years (range: 31-119 months). The initial histology of the B3 lesion influenced the subsequent occurrence of a malignant lesion during follow-up (p < 0.038). The highest malignancy-developing rate was observed in atypical ductal hyperplasia (ADH) (24%, 19/79), while all other B3-lesions had malignant findings ipsi- and contralateral between 0% and 6%. The results were not influenced by the VAB method (Mx-, US-, magnetic resonance imaging-guided), the radiological characteristics of the lesion, or the age or menopausal status of the patient (p > 0.12). Conclusion: With a low risk of <6% of developing malignancy, VAB followed by long-term follow-up is a safe alternative to OE for most B3-lesions. A higher malignancy rate only occurred in ADH (24%). Based on our results, radiological follow-up should be bilateral, preferable using the technique of initial diagnosis. As we observed a late peak (6-7 years) of breast malignancies after B3-lesions, follow-up should be continued for a longer period (>10 years). Knowledge of these long-term outcome results will be helpful in making treatment decisions and determining the optimal radiological follow-up interval.