Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

Ipsilateral breast tumor recurrence after breast-conserving surgery: insights into biology and treatment.

Despite modern surgical and irradiation techniques, ipsilateral breast tumor recurrence (IBTR) accounts for 5-15% of all cancer recurrence in women treated with breast conservative treatment. Historically, this event has been treated definitively with salvage mastectomy and completion axillary clearance. However, many local recurrences are small and without nodal involvement at presentation. Thus, there has been an interest in performing a surgical de-escalation procedure in the breast and the axilla. The current guidelines do not provide detailed descriptions and treatment suggestions for these selected patients, resulting in inconsistent treatment strategies. Moreover, the methods to define true recurrence (TR) and new primary tumor (NP) for IBTR remain controversial. Most developed classification methods mainly rely on clinical and pathological criteria, limiting the accuracy of the discerption and causing misclassification. In this editorial, we will discuss the current trends in surgical de-escalation for patients with IBTR. Moreover, we will focus on recent IBTR innovations, highlighting molecular-integrated classification and multimodal staging methods for clinical practice and postoperative surveillance strategies.

Omission of axillary surgery for ipsilateral breast tumor recurrence with negative nodes after previous breast-conserving surgery: is it oncologically safe?

PURPOSE: Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR. METHODS: We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS) from 2010 to 2018. Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between the SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups. RESULTS: A total of 154 IBTR patients were eligible for final analysis. Compared to the no SAS group, SAS group was less likely to undergo ALND (15.1 vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p = 0.03), and were more likely to have discordant molecular subtype (35.8 vs 12.9%, p = 0.001) and different quadrant location (37.7 vs 19.8%, p = 0.02) with primary tumor. However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. No significant differences were observed in LRRFS, DMFS or OS between the two groups. CONCLUSION: For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS but comparable LRRFS, DMFS, and OS. These results support a wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.

Spatiotemporal Patterns of Loco-Regional Recurrence After Breast-Conserving Surgery.

BACKGROUND: Loco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis. METHODS: To delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype. RESULTS: With a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery. CONCLUSIONS: LRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

Value of stereotactic 11-gauge vacuum-assisted breast biopsy in non-palpable suspicious calcifications: an eight-year single institution experience with 587 patients.

BACKGROUND: Vacuum-assisted breast biopsy (VABB) has been routinely recommended for stereotactic intervention in cases of isolate mammographically-detected calcifications. Herein we aimed to evaluate and compare the diagnostic consistency and accuracy of calcified and noncalcified specimens obtained from same sites of sampling on mammography-visible calcifications. In addition, we presented the biopsy procedure and retrospectively evaluated the usefulness of VABB as well as the complications of this technique over an eight-year experience in our centre. METHODS: This single-institution observational cohort study included 587 patients referred for stereotactic 11-gauge VABB of 594 mammographically-detected calcifications between January 2010 and December 2018. The rate of histopathological underestimation, the false negative, the diagnostic consistency and accuracy between calcified and noncalcified specimens of VABB were comprehensively evaluated based on the surveillance data and final histopathological result of the surgical specimens. RESULTS: In total, 594 biopsy procedures were performed in 587 patients (mean age 46 years, range, 21-80 years). The average number of biopsy specimens was 14.7 (range, 9-21) per lesion. VABB pathological results revealed 471 (79.3%) benign, 39 (6.6%) high-risk, and 84 (14.1%) malignant cases. The diagnostic inconsistency between calcified and noncalcified specimens was 14.6% (105/123) for high-risk and malignant lesions. Furthermore, calcified specimens exhibited higher diagnostic accuracy of malignant lesion as compared with the noncalcified specimens (97.7% versus 82.6%, respectively). Underestimation rate for high-risk lesions and in situ carcinoma was 5.1% and 54.1%, respectively, along with a false negative rate of 6.25%. In addition, mild complications were reported with high patient tolerance. CONCLUSIONS: Stereotactic 11G-VABB might be preferred for the investigation of non-palpable mammographically-detected calcifications in terms of accuracy and safety profile. The high prevalence of diagnostic discordance between the specimens with and without calcifications revealed a higher value of calcified specimens in diagnosing high-risk and malignant calcifications.

A nomogram to predict adjuvant chemotherapy recommendation in breast cancer patients with intermediate recurrence score.

OBJECTIVE: The indication of adjuvant chemotherapy recommendation (ACR) in breast cancer patients with intermediate recurrence score (RS) is controversial. This study investigated the relationship between routine clinicopathological indicators and ACR, and established a nomogram for predicting the probability of ACR in this subset of patients. METHODS: Data for a total of 504 consecutive patients with intermediate RS from January 2014 to December 2016 were retrospectively reviewed. A nomogram was constructed using a multivariate logistic regression model based on data from a training set (378 cases) and validated in an independent validation set (126 cases). A Youden-derived cut-off value was assigned to the nomogram for accuracy evaluation. RESULTS: The multivariate logistic regression analysis identified that age, histological grade, tumor size, lymph node (LN) status, molecular subtype, and RS were independent predictors of ACR. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.286. The area under the curve (AUC) values were 0.905 [95% confidence interval (95% CI): 0.876-0.934] and 0.883 (95% CI: 0.824-0.942) in the training and validation sets, respectively. The accuracies of the nomogram for ACR were 84.4% in the training set and 82.1% in the validation set. CONCLUSIONS: We developed a nomogram to predict the probability of ACR in breast cancer patients with intermediate RS. This model may aid the individual risk assessment and guide treatment decisions in clinical practice.