Breast Cancer Research and Treatment最新文献

Purpose: Due to biological heterogeneity of breast carcinoma, predicting the individual response to neoadjuvant treatment (NAT) is complex. Consequently, there are no comprehensive, generally accepted practices to guide post-treatment follow-up. We present clinical and histopathological criteria to advance the prediction of disease outcome in NA-treated breast cancer.

Methods: A retrospective consecutive cohort of 257 NA-treated Finnish breast cancer patients with up to 13-year follow-up and the corresponding tissue samples of pre- and post-NAT breast and metastatic specimen were evaluated for prognostic impacts. All relevant clinical and biomarker characteristics potentially correlated with tumor response to NAT, course of disease, or outcome of breast cancer were included in the statistical analyses.

Results: The results highlight the intensified characterization of distinguished prognostic factors and previously overlooked histological features, e.g., mitotic and apoptotic activity. Particularly, decreased PR indicated 3.8-fold (CI 1.9-7.4, p = 0.0001) mortality risk, and a > 10.5-year shorter survival for the majority, > 75% of patients (Q1). Clinically applicable prognostic factors both preceding and following NAT were identified and compiled into heat maps to quantify mortality and recurrence risks. Combinations of risk factors for aggressive disease were exemplified as an interactive tool (bcnatreccalc.utu.fi) to illustrate the spectrum of disease outcomes.

Conclusion: The results emphasize the value of comprehensive evaluation of conventional patient and biomarker characteristics, especially concerning re-assessment of biomarkers, risk-adapted surveillance, and personalized treatment strategies. Future personalized NA-treatment strategies might benefit from models combining risk-adapted surveillance data and post-NAT re-assessed biomarkers.

Purpose: This study aimed to analyze changes in serum estradiol (E2) levels during concurrent vaginal estradiol therapy and adjuvant letrozole in postmenopausal breast cancer (BC) patients with vulvovaginal atrophy (VVA). Secondary objectives included assessing the effects of therapy on vaginal atrophy, quality of life (QoL) and menopause-related symptoms.

Methods: 20 postmenopausal patients undergoing adjuvant letrozole therapy and experiencing VVA symptoms were treated with vaginal estradiol for 12 weeks. Gynecologic examination and symptom screening were conducted at baseline and after 12 weeks. Serum E2 levels were analyzed at baseline, and at two, four, eight, and 12 weeks. E2 levels were measured using both a routine liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and a highly sensitive (hsE2-MS) LC-MS/MS method.

Results: At baseline, serum E2 levels, measured with hsE2-MS, were below the lower limit of quantification (LLOQ) in all patients. E2 remained below LLOQ throughout the treatment period in three patients (15%). Persistent E2 elevation above LLOQ was observed in six patients (30%), while isolated E2 elevations occurred in 10 patients (50%). One patient experienced transient E2 elevation in two sporadic measurements. Serum E2 variations were shown by using both LC-MS/MS methods. Vaginal pH, vaginal maturation index (VMI), and VVA symptoms significantly improved during treatment.

Conclusion: Intravaginal estradiol therapy (10ug) during adjuvant letrozole resulted in transient increases in systemic E2 levels among early BC patients with VVA. Highly sensitive LC-MS/MS is a promising method for monitoring E2 levels during aromatase inhibitor (AI) therapy.

Purpose: Understanding real-world treatment patterns and their effectiveness in HR + HER2- advanced breast cancer (aBC) in Canadian patients.

Patient and methods: This was a multi-center, observational, prospective cohort study including men and pre-/peri-/postmenopausal women with HR + HER2- aBC receiving endocrine therapy (ET) or ET + targeted therapy (ET + TT). The primary objective was duration of treatment (DOT) with ET and ET + TT. Sequence of therapies, treatment patterns, and Overall Survival (OS) were also evaluated.

Results: DOT was prolonged in patients receiving ET + TT compared to ET (median DOT: ET + TT 397 days vs ET 192 days; Log-Rank test p value < .0001; HR = 0.66; 95% CI; 0.52, 0.85). An extended DOT was observed in ET + CDK4/6i subgroup when compared to ET (median DOT: ET + CDK4/6i 601 days vs ET 192 days; Log-Rank test p value < .0001). This increase was statistically significant irrespective of line of therapy at baseline (1L: median DOT: ET + CDK4/6i: 649 days vs ET: 217 days, p value =  < .0001; 2L: median DOT: ET + CDK4/6i: 487 days vs ET: 203 days, p value = 0.0013; 3L: median DOT: ET + CDK4/6i: 597 days vs ET: 143 days therapy: p value = 0.0006). ET alone and ET + CDK4/6i were the most frequently administered therapies in both 1st (ET alone: 43.5% and ET + CDK4/6i: 43.3%) and 2nd lines (ET alone: 36.3% and ET + CDK4/6i: 24.6%). Among patients who received at least one CDK4/6i in 1st, 2nd, or 3rd line, CDK4/6i were mostly administered in 1st line (61.9%) and 2nd line (38.5%).

Clinicaltrials: gov ID: NCT02753686; Registration Date:20-04-2016.

Conclusion: Results support current treatment recommendations of early introduction of CDK4/6i in HR + /HER2- aBC.

Background: In New Zealand, BreastScreen Aotearoa (BSA), a biennial national breast screening programme, was implemented in 1998. This study examines the incidence trends of ductal carcinoma in situ (DCIS) in New Zealand women from 1999 to 2022.

Methods: All women with a primary diagnosis of DCIS over the 24-year study period were identified from the New Zealand Cancer Registry and BSA records. Age-standardised incidence rates (ASIR), detection rates (ASDR) and average annual percent changes were calculated.

Results: The annual ASIR was 13.5 per 100,000 New Zealand women, and increased by 0.91% (95% confidence interval (CI): 0.26%, 1.66%) annually. Among women aged 45-69 years during 2006-2022, the annual ASIR was 36.3 for programme-detected DCIS, increasing 1.29% (95%CI: 0.13%, 2.73%) per year, and 14.2 for non-programme-detected DCIS, with no significant changes over the study period. The programme-detected ASIRs were highest for Pacific (38.6), Asian (38.2), and Māori (38.0) women. The programme ASDR was 0.55 per 1000 women screened, with no significant changes over time, and was highest for Asian (0.69), and Māori and Pacific (both at 0.65) women.

Conclusion: DCIS incidence increased in New Zealand women from 1999 to 2022, driven by an increase in screening participation, and varied by ethnicity.

Purpose: Among women in Argentina, the most common cancer is breast cancer (BC) with 21,631 new cases and 6436 deaths per year. The ovarian cancer (OC) is fifteenth in frequency. The contribution of cancer-related large genomic rearrangements (LGRs) of the BRCA1/BRCA2 genes and the 1100delC allelic variant in the CHEK2 gene has not yet been widely studied in our population.

Methods: LGRs in the BRCA1/BRCA2 genes and the CHEK2 1100delC variant were analyzed using the MLPA technique in 85 unselected Argentinian BC/OC patients.

Results: A pathogenic genetic variant (PV) was found in eleven out of 85 (12,9%) patients, 10 were LGRs in the BRCA1 gene, 9 deletions and one duplication and one the CHEK2 1100delC. Large deletions of exons 1-2 and 15 in BRCA1 gene were recurrent anomalies in our series.

Conclusions: LGRs in the BRCA1 gene contributed significantly to the burden of PVs responsible for the development of BC and OC in our study population. On the other hand, the 1100delC variant in CHEK2 was observed at a very low frequency in our series formed mainly by the Spanish, Italian and Amerindian ethnic groups.

Purpose: Microsurgical reconstruction, including vascularized lymph node transfer (VLNT) and lymphaticovenous anastomosis (LVA), have emerged as promising treatment options for chronic breast cancer-related lymphedema (BCRL). Despite their clinical relevance, the precise timelines for patient improvement following these interventions remain rather unexplored. Therefore, the goal of this study was to compare the long-term outcomes and improvement patterns over time of VLNT versus LVA to lay open potential differences and aid in personalized counseling of future patients.

Methods: A prospectively maintained, encrypted database was analyzed for patients with chronic BCRL treated with either VLNT or LVA with a minimum follow-up of one year. Patient-specific variables, such as body weight and circumferential arm measurements at distinct locations on both arms were documented preoperatively and on regular postoperative outpatient follow-ups.

Results: This study comprised 112 patients, of which 107 patients fully completed the one-year follow-up period. Both VLNT and LVA achieved significant arm size reductions. LVA showed an early peak in effectiveness within the first three months, followed by a subsequent decrease and eventual stabilization. Contrarily, VLNT exhibited a distinct pattern with two significant peaks at three and eighteen months.

Conclusions: VLNT and LVA are both effective in long-term lymphedema management, yet they demonstrate marked differences in the timing of improvement. VLNT shows a delayed but more durable response, in contrast to the greater but shorter-lasting surge in effectiveness achieved by LVA. Interestingly, VLNT demonstrates an earlier onset of therapeutic impact than previously understood.

Purpose: To inform decision making around mammography-screening frequency and cessation, we previously used Fine-Gray competing-risk regression to develop and validate a model to estimate older women's 10-year risk of breast cancer and their competing risk of non-breast cancer (non-BC) death. Here, we aimed to understand the amount of incident breast cancer and non-BC death risk explained by our model among women ≥ 65y.

Methods: We included women ≥ 65y who completed the 2004 Nurses' Health Study questionnaire (NHS, n = 59,662) or who participated in the Women's Health Initiative-Extension Study (WHI-ES, n = 82,528). We calculated our model's full and risk factor-specific population attributable risk (PAR%) for incident breast cancer and non-BC death.

Results: Mean age of the NHS participants was 73.5y (SD 5.2); 3.1% were diagnosed with breast cancer and 26.1% experienced non-BC death within 10 years. Mean age of WHI-ES participants was 73.6y (SD 5.4); 4.2% were diagnosed with breast cancer and 17.7% experienced non-BC death within 10 years. The full-model PAR% for breast cancer was 58.8% (22.7-80.6) in NHS and 54.8% (24.8-75.2%) in WHI-ES. Modifiable risk factors explained approximately 1/3 of breast cancer risk; BMI ≥ 30 had a PAR% of 6.5% (3.1-9.9%) in NHS and 12.2% (8.5-16.0%) in WHI-ES. For non-BC death, the full-model PAR% was 94.2% (91.4-96.1%) in NHS and 86.2% (80.9-90.0%) in WHI-ES.

Conclusions: Our competing-risk model explained the majority of breast cancers and non-BC deaths in women ≥ 65y, and we identified risk factors (e.g., elevated BMI) that may be targeted to reduce the burden of breast cancer in older women.

Background: Human epidermal growth factor receptor 2 (HER2)-negative operable breast cancer (BC) patients with germline BRCA1/2 pathogenic variants may benefit from adjuvant olaparib treatment. However, data about how many patients were eligible for olaparib treatment in operable BC patients with BRCA1/2 variants after neoadjuvant chemotherapy (NACT) is lacking.

Methods: A total of 341 operable BC with germline BRCA1/2 pathogenic variants who received NACT at our institute between October 2003 and May 2015 were included. Pathological complete response (pCR) and survival were estimated.

Results: Of the 341 BRCA1/2 carriers (BRCA1: 139; BRCA2: 202), 295 (88.1%) cases exhibited HER2-negative BC in the entire cohort. The most common subtype was triple-negative (TN) BC (62.0%) for BRCA1 carriers and hormone receptor (HR)-positive/HER2-negative BC (68.2%) for BRCA2 carriers, respectively. The pCR rate were 39.6% for BRCA1 carriers and 28.2% for BRCA2 carries. The pCR rate in TNBC, HR-positive/HER2-negative BC, and HER2-positive BC were 45.0%, 22.3%, and 45.0% in the entire cohort, respectively. Of these HR-positive/HER2-negative BC patients, 16.0% had non-pCR and exhibited CPS+EG≥3. Overall, 31.9% of the HER2-negative BC cohort were potential candidates for adjuvant olaparib, with 44.0% for BRCA1 carriers and 22.9% for BRCA2 carriers. Furthermore, patients with non-pCR exhibited a worse survival regardless of TNBC and HR-positive/HER2-negative BC disease, especially for HR-positive/HER2-negative BC with CPS+EG≥3.

Conclusion: Approximately one-third of HER2-negative BC patients with BRCA1/2 pathogenic variants are potential candidates for adjuvant olaparib treatment after NACT, with a higher proportion for BRCA1 carriers compared to BRCA2 carriers.

Background: Transfer RNA (tRNA) fragments (tRFs) are a group of small non-coding RNAs with biological functions. The involvement of tRNAs in cancer has also been recognized, but most studies focused on nuclear tRFs, very few on mitochondrial tRFs.

Methods: We analyzed the TCGA microRNAseq data to identify differentially expressed mitochondrial tRFs (mt-tRFs) in breast tumors and evaluated their associations with the disease outcome. Cox proportional hazards regression was used to determine the associations between mt-tRFs and patient survival while adjusting for clinicopathological variables. Quantitative RT-PCR was developed to measure a specific tRF expression in a validation study.

Results: Our analysis of 1,060 tumor samples from TCGA revealed that mt-tRF-Tyr-GTA-001 (tRF-21-X3OJI8EWB or t00018104) expression, a tRF from mitochondrial tRNA with tyrosine anticodon GTA (mt-tRNA-Tyr-GTA), was significantly lower in breast tumors than the adjacent tissues (p< 0.0001). Patients with low expression had significantly higher risk of death (HR = 1.69, p = 0.0018) regardless of their age at diagnosis, disease stage, tumor grade, and hormone receptor status. This survival association was replicated in an independent study where mt-tRF-Tyr-GTA-001 expression was measured with qRT-PCR. Further analysis suggested that the mt-tRF expression was correlated with ribonuclease ANG and RNase 4 known to cleave tRNAs and upregulated under hypoxia. IPA interrogation of the mt-tRF-Tyr-GTA-001 expression signature indicated the inhibitory effects of mt-tRF-Tyr-GTA-001 on malignant transformation, tumor growth, and cell invasion. In silico analysis showed that the binding targets of mt-tRF-Tyr-GTA-001 included several oncogenic transcription factors (E2Fs, CCNE1, FOXM1). We also found the mt-tRF correlated with the abundances of M0 macrophages and resting mast cells, two of the immune cells known for innate immunity.

Conclusions: In summary, our study suggests that mt-tRF-Tyr-GTA-001, a mitochondrial tRF, may suppress breast cancer progression through its involvement in regulation of cell phenotype and tumor immunity.