Breast Cancer Research and Treatment最新文献

Purpose: Aromatase Inhibitors Associated Musculoskeletal Symptoms (AIMSS) are common side effects among hormone receptor-positive breast cancer patients, significantly affecting patients' treatment adherence and quality of life. The individual genetic susceptibility mechanism underlying AIMSS was not well understood yet. This study aimed to validate the association between genetic polymorphisms and AIMSS among Chinese breast cancer patients.

Methods: This was a cross-sectional study. Participants were recruited from a tertiary hospital in China from May 2023 to June 2024. Musculoskeletal symptoms were measured using the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) among hormone receptor-positive patients receiving aromatase inhibitor therapy. Six genes (i.e., ESR1, ESR2, RANK, OPG, TCL1A and CYP19A1) related 20 SNPs were tested. Multivariate linear regression analysis was used to explore the association between different genotypes and the severity of AIMSS.

Results: Among 171 participants, the standardized M-SACRAH score was 3.33 (IQR 0.00-9.17) and the standardized WOMAC score was 5.83 (IQR 2.08-17.29). Patients carrying the ESR1 rs9340799 AG genotype (vs. AA) had a significant reduction in the severity of hand joint symptoms [adjusted β = -4.51, 95% CI: -8.29, -0.73, p = 0.020] and knee/hip joint symptoms [adjusted β = -4.44, 95% CI: -8.49, -0.39, p = 0.032]. The ESR1 rs2077647 TC genotype (vs. TT) was related to lower level of hand joint symptoms [adjusted β = -5.03, 95% CI: -8.69, -1.37, p = 0.007] and knee/hip joint symptoms [adjusted β = -5.04, 95% CI: -8.97, -1.12, p = 0.012]. The ESR1 rs2234693 TC genotype (vs. TT) [adjusted β = -4.06, 95% CI: -8.09, -0.03, p = 0.049] was associated with lower level of knee/hip joint symptoms. No significant associations emerged between ESR2, RANKL, OPG, TCL1A, or CYP19A1 variants and AIMSS.

Conclusions: This study preliminarily validated the association between ESR1 polymorphisms (rs9340799, rs2077647, and rs2234693) and aromatase inhibitor associated musculoskeletal symptoms in hormone receptor-positive breast cancer among Chinese patients. Future research should focus on dissecting their molecular mechanisms, and integrating genetic data with clinical interventions to optimize the management strategies of musculoskeletal toxicity.

Purpose: For early-stage triple-negative breast cancer (TNBC), the KEYNOTE-522 trial established neoadjuvant pembrolizumab plus chemotherapy (CT), followed by adjuvant pembrolizumab, as the standard of care. Nevertheless, uncertainties remain on how to integrate this regimen with other adjuvant therapies such as capecitabine or olaparib. This study evaluated real-world treatment patterns and safety of adjuvant therapies following neoadjuvant chemoimmunotherapy.

Methods: The Neo-Real study includes patients with TNBC treated with neoadjuvant pembrolizumab plus CT in Brazil and Argentina. This study describes real-world adjuvant treatment patterns and safety; survival outcomes are not reported in this analysis.

Results: Among 726 patients included, 692 underwent surgery, and 62.9% achieved pathologic complete response (pCR). Of those with pCR, 84.8% received adjuvant pembrolizumab alone, while 14.3% received no adjuvant therapy. Among patients with residual disease and no germline BRCA1/2 mutations (n = 207), 57.5% received pembrolizumab plus capecitabine, 26.1% pembrolizumab alone, and 12.6% capecitabine alone. In BRCA1/2-mutated patients (n = 26), 57.7% received pembrolizumab plus olaparib, 19.2% pembrolizumab alone, and 11.5% olaparib alone. Safety data were available for 359 patients. Adjuvant pembrolizumab alone caused a lower incidence of grade ≥ 3 AEs (6.7%) compared with combination regimens (P = 0.002). Drug discontinuation due to toxicity occurred in 5.7%, 11.2%, and 7.7% of patients receiving pembrolizumab, pembrolizumab + capecitabine, and pembrolizumab + olaparib, respectively (P = 0.126).

Conclusion: Most patients with pCR continued adjuvant pembrolizumab, while combination strategies predominated among those with residual disease and were associated with higher rates of grade ≥ 3 AEs. The efficacy of these combined regimens remains to be determined.

Purpose: To evaluate the potential prognostic value of two peripheral immune biomarkers-neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII)-in breast cancer patients treated with neoadjuvant chemotherapy, and to assess their association with pathological complete response (pCR) and other predictive factors. In addition, to determine whether prognostic or predictive differences exist between baseline and post-neoadjuvant values of these biomarkers.

Methods: We analyzed 801 women with early breast cancer treated with neoadjuvant chemotherapy, evaluating clinical and pathological data, survival outcomes, NLR (continuous and categorical) and SII.

Results: Baseline NLR was significantly higher in younger patients, in those with positive pathological nodes, and in the HER2 + /HR - subtype, while baseline SII was elevated in the triple-negative subtype. Post-neoadjuvant chemotherapy (post-NCT) NLR and SII showed only weak associations with estrogen receptor expression, yet both were independently associated with pCR (post-NCT NLR: OR = 0.91; 95% CI: 0.84-0.98; p = 0.02; post-NCT SII: OR = 0.65; 95% CI: 0.47-0.89; p = 0.008). Neither biomarker showed a significant impact on overall or progression-free survival.

Conclusion: Post-treatment NLR and SII may reflect chemotherapy-induced immune changes and are associated with pathological complete response, but their additional predictive value is uncertain, and no prognostic impact was observed.

Introduction: Tucatinib, a small molecule HER2 inhibitor, was approved in inoperable or metastatic HER2 + breast cancer. As many patients have tumors in challenging surgical locations, there is a need for imaging metrics to characterize tucatinib response and microenvironment impact. Molecular imaging can be used to quantify dynamic molecular changes that precede tumor size alterations and can target proliferation (fluorothymidine, [¹⁸F]-FLT), hypoxia (fluoromisonidazole, [¹⁸F]-FMISO) and HER2 expression ([⁸⁹Zr]-Pertuzumab) with positron emission tomography (PET) imaging. The goal of this study is to non-invasively characterize tucatinib response in HER2 + breast cancer and quantify microenvironment modulation with advanced PET imaging.

Methods: Mice with HER2 + human cell line (BT474) or patient derived xenograft (BCM 3472) tumors were treated with 50 mg/kg tucatinib and enrolled into imaging cohorts: imaged with [¹⁸F]-FLT-PET on days 0, 3 and 7, [¹⁸F]-FMISO-PET on days 0, 3 and 7, or [⁸⁹Zr]Zr-Pertuzumab-PET on days 0 and 14. Proliferation, hypoxia and HER2 expression were quantified with standardized uptake value. A Mann-Whitney U Test assessed significance between groups.

Results: Tucatinib-treated human cell line and PDX tumors had significantly decreased hypoxia and proliferation relative to control tumors (p < 0.05). Tucatinib-treated BT474 tumors had significantly decreased HER2 expression (p < 0.05); however, no significant HER2 change was observed in BCM3472 tumors.

Conclusion: Tucatinib significantly decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2 + breast cancer, which can be longitudinally quantified with PET imaging. Our data suggests molecular imaging may improve understanding and prediction of tucatinib response.

Purpose: Trastuzumab-deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that revolutionized the treatment approach for breast cancer. However, the infectious risk associated with T-DXd is unknown. Here, we evaluate the infectious risk of T-DXd against trastuzumab-emtansine (T-DM1), an ADC with an identical monoclonal antibody.

Methods: We conducted a retrospective study of consecutive breast cancer patients who received T-DXd or T-DM1. Demographic data, infection risk factors, infection sites, and opportunistic infections were recorded and compared across treatment groups. Multivariable logistic regression was used to evaluate the association between treatment group and infection, adjusting for clinical risk factors.

Results: 374 patients received T-DXd or T-DM1, with 126 receiving T-DXd alone, 196 receiving T-DM1 alone, and 52 patients receiving both treatments. Patients who received T-DXd did so as higher line of therapy (p < 0.001), was given more in the palliative setting (100% vs 33.7%, p < 0.001), had more prior immunosuppressive systemic treatment (78.6% vs 16.9%, p < 0.001), were exposed to more significant corticosteroid courses (17.2% vs 4.5%, p < 0.001), and had more hospitalizations during treatment (57.3% vs 27.7%, p < 0.001). Patients treated with T-DXd had a higher incidence of total infections (24.4% vs 14.0%, p = 0.01); in the infected population, unadjusted analysis reveals that those treated with T-DXd had more bloodstream infections (33.3% vs 5.9%, p = 0.004) and more infection-related mortality (18.2% vs 0%, p = 0.01). Three patients developed opportunistic infections on T-DXd, and 2 of the 3 were treated concurrently with high-dose corticosteroids. For multivariate analysis, after adjustment for clinically relevant variables and those associated with the outcome in univariate analyses, T-DXd was not associated with an increased risk of infection (OR = 1.89, 95% CI: 0.85-4.32, p = 0.12).

Conclusion: Although patients receiving T-DXd had a higher incidence of infection, no significant difference in infectious risk was found after adjusting for several confounding variables. Infection-related mortality and opportunistic infections were rare and only occurred in the T-DXd cohort. Future prospective studies are warranted to more reliably evaluate the infectious risk of T-DXd compared to T-DM1, particularly as T-DXd is increasingly utilized earlier in the treatment course for breast cancer patients.

Purpose: Triple-negative breast cancer (TNBC) patients with brain metastases have a poor prognosis and limited treatment options. Preclinical and clinical evidence suggests that radiotherapy may act synergistically with immune checkpoint inhibitors.

Methods: We conducted an open-label, single-arm, phase II study of atezolizumab plus stereotactic radiosurgery (SRS) in metastatic TNBC patients with brain metastases. The primary endpoint was progression-free survival (PFS) according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) bi-compartmental model. Secondary endpoints included extracranial objective response rate, overall survival (OS), and safety and tolerability. A safety run-in analysis for dose-limiting toxicity (DLT) was performed after the first 6 patients were enrolled and completed the assessment period.

Results: Six patients were enrolled into the safety run-in phase between May 11, 2018 and October 24, 2019. No DLTs were observed, but the study was closed early due to slow accrual. Patients received a median of 2 atezolizumab cycles (range: 2-16), and SRS was administered to all 6 patients. Treatment-related adverse events (TRAEs) occurred in 4 participants (66.7%); all events were grade 2. The median bi-compartmental PFS was 1.3 months (95% confidence interval (CI): 0.95 - NA) and the median OS was 9.7 months (95% CI: 3.6 - NA). The best observed response by RECIST 1.1 criteria was stable disease ≥ 24 weeks in one participant (16.7%).

Conclusions: Concurrent SRS with atezolizumab was feasible in TNBC patients with brain metastases. However, disease outcomes were poor, and the development of effective therapies for these patients remains a significant unmet medical need.

Clinical trial registry number: https://www.

Clinicaltrials: gov NCT03483012. Trial Open to Accrual: 05/01/2018.

Purpose: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus aromatase inhibitor (AI) is the recommended first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). CDK4/6i head-to-head trials have not been conducted, and randomized controlled trials (RCTs) report inconsistent overall survival (OS) results despite similar effects on the primary endpoint of progression-free survival. Real-world evidence can complement RCTs but selection biases and confounders can challenge interpretation. Target trial emulation applies the principles of RCTs to observational data to overcome such challenges. We emulated a hypothetical target trial to investigate whether causal differences in OS between patients receiving first-line CDK4/6i plus AI exist in the real-world clinical setting.

Methods: We used de-identified data (Flatiron Health mBC Enhanced Data Mart) from patients ≥ 18 years old at primary diagnosis who were treated with first-line palbociclib/ribociclib/abemaciclib plus AI for mBC between 2018 and 2024. Statistical adjustments included stabilized inverse-probability weighting (sIPTW), investigation of missing data mechanisms, and analyses for unmeasured confounders.

Results: 2626 patients were included (palbociclib n = 1686; ribociclib n = 537; abemaciclib n = 403). After sIPTW, baseline characteristics were balanced between groups and there was no observable difference in real-world OS (ribociclib vs palbociclib, adjusted hazard ratio 1.00, 95% CI: 0.81-1.24; abemaciclib v palbociclib: 0.91, 95% CI: 0.74-1.14). Results were consistent after sensitivity analyses.

Conclusion: Using target trial emulation, real-world OS is similar with palbociclib/ribociclib/abemaciclib plus AI. These findings may contribute to the development of combination strategies to improve clinical outcomes and to guide clinical decision-making.

Purpose: Estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer (MBC) shows variable outcomes after first-line CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET). The prognostic role of PAM50 intrinsic subtypes (IS) in this setting remains unestablished. We evaluated IS and biomarker profiles in the SOLTI-1801 CDK-PREDICT cohort, focusing on real-world second- and third-line progression-free survival (rwPFS-2L and rwPFS-3L).

Methods: This multicenter observational study reports a post hoc secondary analysis of ER+ /HER2- MBC patients previously treated with first-line CDK4/6i plus ET. Baseline metastatic biopsies were molecularly profiled (PAM50, CCNE1, PDCD1) using the nCounter platform. rwPFS-2L and rwPFS-3L were defined from initiation of second- or third-line therapy to progression or death. Kaplan-Meier and Cox models assessed associations with clinical, molecular, and treatment variables.

Results: Among evaluable patients (n = 125 for rwPFS-2L; n = 95 for rwPFS-3L), Luminal A/B subtypes represented most cases, while advanced lines showed more aggressive profiles. Median rwPFS-2L was 7.2 months in luminal IS vs. 6.1 in non-luminal (HR 1.40; 95% CI 0.86-2.30); the Basal-like (BL) subtype correlated with significantly shorter rwPFS-2L (HR 3.82; 95% CI 1.07-13.63). In rwPFS-3L, similar trends were seen (6.4 vs. 3.3 months; HR 1.74; 95% CI 0.98-3.08), with BL showing the poorest outcomes (HR 5.63; 95% CI 1.17-27.02). High CCNE1 expression was linked to shorter rwPFS-2L (HR 1.22; 95% CI 1.02-1.47). Targeted agents were frequent in 2L (51%) and capecitabine in 3L (36%), while endocrine monotherapy yielded poorest rwPFS.

Conclusions: Outcomes after CDK4/6i progression differ by PAM50 IS, supporting its role in guiding post-progression treatment.

Background: Patients with localized breast cancer receiving adjuvant chemotherapy often experience sleep disturbances, especially insomnia, which significantly impacts quality of life. This study primarily aimed to evaluate the effects of a 12-week exercise program on insomnia, with secondary outcomes on sleep quality, anxiety/depression, fatigue, pain, and exercise adaptation.

Methods: In this randomized controlled multicenter trial, 20 women with non-metastatic breast cancer and clinically diagnosed insomnia were assigned to a control or training group. The training group underwent a 12-week supervised intermittent aerobic exercise program during chemotherapy. The primary outcome was objective total sleep time; secondary outcomes included insomnia severity, sleep architecture, sleep quality, anxiety/depression, fatigue, pain, and cardiorespiratory capacity. Assessments were performed before chemotherapy (T-1), at baseline (T0), and post-intervention (T3) using polysomnography, actigraphy, validated questionnaires, and a maximal graded exercise test.

Results: The prevalence of clinical insomnia increased from 47% before diagnosis to 71% at T-1, reaching 100% at T0. Total sleep time did not increase after training (p = 0.97), although sleep fragmentation decreased. Clinical improvement was observed in physical and activity-related fatigue. Finally, both submaximal exercise adaptation parameters (power and VO₂/HR) and maximal parameters (power, VO₂ peak, VO₂/HR) significantly improved.

Conclusions: The training did not increase total sleep time, likely due to insomnia's multifactorial origin. However, training yielded beneficial effects on objective sleep quality and exercise-induced adaptation. Future research is needed to investigate the various etiologies of insomnia to develop tailored and personalized management approaches.

Clinical trials number: NCT04867096.