The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed.

Prognostic value of structural variants in early breast cancer patients.

Genomic analysis of structural variants(SVs) in breast cancer (BC) patients has been conducted, but the relationship between genomic alterations and BC prognosis remains unclear. We performed RNA sequencing of 297 early BC fresh-frozen tissues. We identified SVs using three tools (STAR.Arriba, STAR.fusion, and STAR.SEQR) with the COSMIC and Mitelman databases as guide references. We found a median of five to eight fusions per sample. In BC intrinsic subtypes, normal subtype had the fewest fusions (median: 1, interquartile range [IQR]: 0, 3) followed by luminal A (median: 5.5, IQR: 2.75, 10.25), luminal B (median: 9, IQR: 6, 16.5), HER2-enriched (median: 9, IQR: 6, 16.5) and basal (median 10, IQR: 6, 15.5) subtypes (p < 0.05). Intrachromosomal fusion was more frequent observed rather than interchromosomal fusion. In location, chromosome 17 had the most fusions followed by chromosome 1 and 11. When samples were divided into high and low fusion groups based on a cut-off value of 11 fusions, five-year event-free survival (5Y-EFS) was 68.1% in the high fusion group (n = 72) and 80.1% in the low fusion group (n = 125) (p = 0.024) while 75.6% among all patients (95% confidence interval: 0.699, 0.819). Among BC subtype, TNBCs with more fusions had shorter EFS compared to those with fewer fusions (5Y-EFS rate: 65.1% vs. 85.7%; p = 0.013) but no EFS differences were observed in other BC subtypes. ESTIMATE ImmuneScore was also associated with the number of fusions in TNBC (p < 0.005) and TNBCs with high ImmuneScore had better 5Y-EFS compared to those with low ImmuneScore (p = 0.041). In conclusion, diverse fusions were observed by BC subtype, and the number of fusions was associated with BC survival outcome and immune status in TNBC.

Endoxifen Concentration is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients.

Purpose: The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dosage. However, the clinical significance of endoxifen on the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication. Materials and Methods: The study included 478 breast cancer patients, and tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff. Results: An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% CI, 77.0-89.9%) and 88.3% (95% CI, 83.3-93.5%) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor affecting prognosis, which was adjusted with other clinical characteristics. Conclusion: Endoxifen could serve as a marker for appropriate tamoxifen treatment, and an endoxifen cutoff of 21.00 ng/mL could be advantageous in prognostication. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying a suboptimal concentration.

The Effects of National Insurance Coverage Expansion and Genetic Counseling's Role on BRCA1/2 Mutation Tests in Breast Cancer Patients.

PURPOSE: This study aims to evaluate the impact of South Korea's national insurance coverage (NIC) expansion and the addition of genetic counselors on BRCA1/2 mutation testing rates in breast cancer patients. MATERIALS AND METHODS: A retrospective review was conducted at the Samsung Medical Center (SMC), dividing patients into three groups: pre-NIC expansion, post-NIC expansion, and post-extra genetic counselor involvement. The number of BRCA1/2 tests performed and the detection rates among newly diagnosed and follow-up patients, particularly focusing on triple-negative breast cancer (TNBC) cases, were analyzed. RESULTS: Post-NIC expansion, there was a significant increase in BRCA1/2 testing rates, with a gradual rise in detection rates while maintaining statistical significance. TNBC patients under 60 experienced substantial increases in testing rates. The number of follow-up patients recalled for testing also rose significantly after the extra genetic counselor involvement. Additionally, NIC expansion increased insurance coverage for TNBC patients, enhancing accessibility to testing. CONCLUSION: The study highlights the positive impact of NIC expansion and genetic counselor involvement on BRCA1/2 mutation testing rates and subsequent patient management. Addressing financial barriers to testing and incorporating genetic counseling significantly improve patient outcomes. This model provides a potential strategy for enhancing early detection and personalized treatment for breast cancer patients with BRCA1/2 mutations, contributing to global cancer management efforts.

A 10-Gene Signature to Predict the Prognosis of Early-Stage Triple-Negative Breast Cancer.

Purpose: Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies. Materials and Methods: In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing. Results: By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor ß diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores. Conclusion: Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.

Long-term oncologic outcomes of unselected triple-negative breast cancer patients according to BRCA1/2 mutations.

Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10-20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3-152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers (P = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P < 0.0001). Interestingly, among 29 patients with CBC recurrence, 24 patients (82.8%) had recurring TNBC subtype and among the CBC recurrence patients, 19 patients (65.5%) resumed chemotherapy. In the TNBC subtype, appropriate genetic testing and counseling are pivotal for surgical decisions like risk-reducing mastectomy (RRM). Furthermore, long-term surveillance is warranted, especially in BRCA1/2 carriers who did not receive RRM.

Comprehensive Young Age Breast Cancer registry from clinical, genomics, and patient-reported outcomes measured with 15 years follow-up: the CHARM cohort profile.

BACKGROUND: In recognition of the distinct clinical challenges and research gaps in young breast cancer (YBC) patients, we established the Comprehensive Young Age Breast Cancer (CHARM) registry to collect prospective data. METHODS: This prospective cohort included patients who were newly diagnosed with histologically confirmed breast cancer without prior treatment at the Samsung Medical Center (SMC) in April 2013. We included patients who were either 40 years old or younger at the time of diagnosis, pregnant at breast cancer diagnosis or diagnosed with breast cancer within 1 year of delivery. All data were collected using Medidata's Rave Electronic Data. Clinical data were obtained from electronic medical records. Two experienced pathologists reviewed the pathologic data. Bone mineral densitometry tests have been conducted annually. To obtain multi-omics data, tumor tissues and blood samples were prospectively collected from consenting patients in the registry during surgery. The fertility-related factor also collected collaborated with the Department of Obstetrics and Gynecology. Anti-Müllerian hormone, estradiol, follicle-stimulating hormone, and luteinizing hormone levels were measured using an additional blood sample from baseline to last follow-up. Patient-reported outcomes were assessed using mobile questionnaires. RESULTS: A total of 1868 participants were included in the SMC YBC study. The average (standard deviation) age was 35.57 (3.79) and 99.8% of the participants were premenopausal. Among them, 1062 participants completed the PRO questionnaires. CONCLUSIONS: The SMC YBC cohort serves as a comprehensive registry for YBC to optimize care and improve knowledge regarding the management of YBC.

Outcomes of whole breast radiation therapy in Asian breast cancer patients with prior cosmetic implants.

BACKGROUND: As breast augmentation has become more popular, an increasing number of women with augmented breasts require treatment for breast cancer. This study aimed to assess the outcomes of postoperative whole breast radiation therapy (WB-RT) in Asian patients with breast cancer who underwent prior cosmetic breast implantation. METHODS: We retrospectively reviewed the medical records of 61 patients with breast cancer who had prior cosmetic breast implants (prior-CBI) and underwent breast-conserving surgery (BCS) and WB-RT between 2015 and 2020. The median implant volume was 238.8 cc, with a median interval of 84.7 months between the prior-CBI and BCS. WB-RT was administered with either conventional fractionation (CF-RT) at 50 Gy in 25 fractions (N = 36) or hypofractionation (HF-RT) at 42.6 Gy in 16 fractions (N = 25). The incidences of implant-related complications (IRC) and their contributing factors were analyzed. RESULTS: After a median follow-up of 43.5 months, the 3-year cumulative incidences of IRC and implant loss were 17.2% and 4.9%, respectively. Among the four (6.6%) patients who opted for implant removal after RT, three were potentially related to RT-related capsular contracture. There was no difference in the 3-year cumulative IRC rates following CF-RT and HF-RT (12.2% and 26.7%, respectively; p = 0.120). The risk factors for IRC included a larger implant size (> 260 cc) and a higher ratio of breast tissue to implant volume. CONCLUSIONS: This study demonstrated a favorable safety profile of WB-RT for treatment of breast cancer in Asian women with prior-CBI. The integration of HF-RT following BCS was thought to be a feasible approach.

Oncologic Outcomes of Immediate Breast Reconstruction in the Setting of Neoadjuvant Chemotherapy: A Long-term Follow-up Study of a Matched Cohort.

PURPOSE: Despite the increasing use of immediate breast reconstruction (IBR), its oncologic safety in the setting of neoadjuvant chemotherapy (NACT) needs to be comprehensively clarified in breast cancer management. The objective of the present study was to analyze the oncologic safety of IBR following NACT. METHODS: In total, 587 patients with breast cancer who underwent a total mastectomy (TM) with IBR after NACT between 2008 and 2017 at a single institution were retrospectively reviewed. The reviewed patients with IBR following skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) were matched 1:3 to patients who underwent TM alone after NACT. Matching variables included age, clinical T and N stages before NACT, response to NACT, pathologic T and N stages, and molecular subtypes. RESULTS: After propensity score matching, 95 patients who underwent IBR following SSM/NSM after NACT (IBR group) and 228 patients who underwent TM alone after NACT (TM group) were selected. The median follow-up period was 73 (range, 5-181) months after matching. After matching, there were no significant differences between the two groups in 5-year locoregional recurrence-free survival (88.8% vs. 91.2%, p = 0.516), disease-free survival (67.3% vs. 76.6%, p = 0.099), distant metastasis-free survival (71.9% vs. 81.9%, p = 0.057), or overall survival (84.1% vs. 91.5, p = 0.061) rates. In multivariate analyses, conducting IBR was not associated with increased risks for locoregional recurrence, any recurrence, distant metastasis, or overall death. CONCLUSION: Our findings suggest that IBR following SSM/NSM elicits comparable long-term oncologic outcomes to those of TM alone in the setting of NACT.