Breast Cancer Research最新文献

Background: Trastuzumab, combined with chemotherapy, is the current standard treatment for both metastatic and early-stage HER2-positive (HER2 +) breast cancer. One of the mechanisms of action of trastuzumab is antibody-dependent cellular cytotoxicity (ADCC), which involves engaging FcγRIIIA (CD16) on natural killer (NK) cells. A competent immune system and properly functioning NK cells are crucial for effective ADCC, as they can influence favorable clinical outcomes. Resistance to trastuzumab often develops after about one year. We previously reported that elevated levels of miR-19a-3p in the serum of patients with metastatic HER2 + breast cancer treated with trastuzumab were associated with a favorable prognosis. Here, we aim to identify the mechanism and the immune cells responsible for elevated serum levels of miR-19a-3p.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy individuals were used to isolate naïve CD4 + T cells and NK cells. Naïve CD4 + T cells were polarized into CD4 + Th1 and CD4 + Th2 cells. NK cells were utilized for the ADCC assay. Levels of transcription factors, cytokines, and miR-19a-3p were measured using RT-qPCR. Surface markers and cytokines were analyzed by flow cytometry to characterize immune cell phenotypes.

Results: In vitro NK cell-mediated ADCC resulted in increased levels of miR-19a-3p released into the supernatants after killing breast cancer cells. In vitro polarized CD4 + Th1 cells expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. Over a long-term in vitro culture (24 days), anti-CD3/CD28 restimulation sustained higher levels of miR-19a-3p in CD4 + Th1 cells compared to CD4 + Th2 cells and their respective supernatants. CD4 + Th1 cells developed a central memory T (T_CM) phenotype (CD45RO + CCR7 + CD62L +) and expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. In patients with HER2 + metastatic breast cancer, those with elevated serum levels of miR-19a-3p and a favorable prognosis had a larger percentage of circulating activated T cells and NK cells in their blood compared to patients with lower serum levels of miR-19a-3p and a poor prognosis. The small cohort (n = 15) limits the statistical power of our retrospective study.

Discussion: Our findings suggest that elevated levels of miR-19a-3p in the serum of patients with HER2 + metastatic breast cancer may result from effective NK cell-mediated ADCC and activation of CD4 + Th1 cells, which could be responsible for the anti-tumor immune response associated with a favorable prognosis. Blood levels of miR-19a-3p might help identify breast cancer patients who have effective trastuzumab-induced anti-tumor immune responses.

Background: ESR1 alterations present a common mechanism of resistance to endocrine therapy (ET) in hormonally driven tumors. The clinical significance of these alterations continues to evolve with newly approved targeted therapies and a range of ongoing investigational trials.

Methods: A retrospective study of 2574 breast cancer (BC) and 1110 gynecologic cancer samples that underwent whole exome and whole transcriptome profiling was conducted to assess the distribution of ESR1 and associated co-alterations in local (primary breast or regional lymph node) versus metastatic BC samples and in the major BC subtypes. Prior treatment history was unknown.

Results: ESR1 alterations were present in 6.2% (n = 159/2574) of BC samples and 3.4% (n = 38/1110) of gynecologic cancer samples. In HR + /HER2- BC, ESR1 alterations overall and ESR1 missense mutations were more frequent in samples from metastatic compared to local/regional sites (overall: n = 86/321 (26.8%) and n = 53/1427 (3.7%), respectively (P < 0.001); missense: n = 72/321 (22.4%) and n = 20/1427 (1.4%), respectively (P < 0.001)). Whole transcriptome sequencing detected ESR1 fusion genes in 2.1% (n = 55/2574) of BC samples and in 1.9% (n = 21/1110) of gynecologic cancer samples, and CCDC170 was the most common fusion partner in both cancer types. In HR + /HER2- BC, ESR1 fusions were more common in metastatic samples compared to local/regional (n = 17/321 (5.3%) and n = 29/1427 (2.0%), respectively; P < 0.001). Evaluation of 21 therapeutically actionable biomarkers identified co-alterations enriched in ESR1-altered HR + /HER2- BC, including FGF3/4/19 and CCND1 amplifications. No significant co-alterations were found in gynecologic cancer samples.

Conclusions: ESR1 alterations were most frequent in HR + /HER2- BC samples and missense mutations were more frequent in metastatic samples, consistent with their role in ET resistance and disease progression. ESR1 alterations co-occurred with therapeutically relevant alterations in other genes that may help inform clinical decision-making. Gynecologic tumors harbored ESR1 alterations that have prognostic and potentially therapeutic relevance.

Background: In the years following pregnancy, breast cancer risk is elevated, particularly for hormone receptor negative (HR-) tumors. Exposure to high maternal circulating estrogens, when the breast is vastly remodeling in structure and morphology, has been associated with HR- tumor risk. Estrogen metabolite profiles in nonpregnant women, notably the ratio of 2:16 hydroxylation (OH) pathway metabolites, are associated with postmenopausal breast cancer development; whether estrogen metabolism during pregnancy influences subsequent HR- breast cancer risk is unknown.

Methods: We conducted a population-based case-control study in women 19-39 years identified in the Finnish Maternity Cohort Biobank and linked with the Finnish Cancer Registry to identify breast cancer diagnoses within 20 years of pregnancy. Estrogens and metabolites were measured using highly reliable and sensitive LC-MS/MS methods in serum collected during the first and second trimesters of pregnancy. Included were invasive, ER-/PR- breast cancer cases (n = 449) and controls (n = 449) matched on maternal age at index pregnancy, parity, calendar year of serum collection, gestational week of blood collection, and number of sample freeze/thaw cycles. Associations between the estrogens and breast cancer risk were estimated using odds ratios (ORs) with 95% confidence intervals (CIs) from conditional logistic regression models.

Results: The median years of follow-up between blood collection and breast cancer diagnosis/control selection was 9 (range 0-19). Ninety-three percent of cases were < 50 years of age at breast cancer diagnosis. Total estrogens were positively associated with ER-/PR- breast cancer (OR associated with a doubling of total estrogens 1.16; 95% CI 1.02-1.32), as were metabolites in the 16-pathway including estriol [OR 1.11; 95% CI 1.01-1.22], 16-epiestriol [OR 1.11; 95% CI 1.01-1.21)], 17-epiestriol [OR 1.06; 95% CI 1.01-1.13], and total 16-hydroxylation pathway metabolites [OR 1.11; 95% CI 1.00-1.24]. There was no clear association with the ratio of 2:16 hydroxylation pathway metabolites. Some associations differed by parity, age at diagnosis, and gestational timing of blood collection, but interactions were not statistically significant. Results were similar when restricted to cases occurring within 15 years since pregnancy.

Conclusion: This prospective study demonstrated positive associations of estrogen metabolites in pregnancy and risk of mostly premenopausal ER-/PR- breast cancer, but the magnitudes varied by metabolite. No strong or consistent pattern for one metabolic pathway emerged suggesting that total estrogen concentrations during pregnancy are associated with subsequent HR- breast cancer development, regardless of how they are metabolized.

Background: EGFR is overexpressed in TNBC, and "naked" anti-EGFR monoclonal antibodies have been evaluated in clinical trials with dismal effectiveness. Matuzumab is an anti-EGFR monoclonal antibody that can be used to develop theranostics. We posit that compared with "naked" antibodies, [²²⁵Ac]Ac-Macropa-matuzumab will be effective against EGFR-positive TNBC xenografts.

Methods: We developed and characterized [²²⁵Ac]Ac-Macropa-matuzumab. Cytotoxicity was studied in EGFR-positive MDA-MB-468 (high EGFR density), MDA-MB-231 (medium EGFR density) and MCF-7 (low EGFR density) 2D monolayer cells and 3D spheroids using live-cell imaging. Biodistribution was carried out in naïve female BALB/c and athymic nude BALB/c tumor-bearing mice. Radioimmunotherapy was studied after administration of 2 × 13 kBq [²²⁵Ac]Ac-Macropa-matuzumab dose and compared with irrelevant IgG and saline-treated controls. Safety was evaluated in naïve female BALB/c mice.

Results: Biodistribution of [²²⁵Ac]Ac-Macropa-matuzumab in mice bearing MDA-MB-468 and MDA-MB-231 xenografts showed the highest tumor uptake at 120 h post-injection (p.i.) and was 48.3 [Formula: see text] 28.6%IA/g and 39.0 [Formula: see text] 9.1%IA/g, respectively. In vitro, [²²⁵Ac]Ac-Macropa-matuzumab suppressed the growth of EGFR-positive spheroids with an IC₅₀ of: MDA-MB-468 (5.3 [Formula: see text] 6.6 kBq/mL) ∼ MDA-MB-231 (4.9 [Formula: see text] 6.4 kBq/mL) < MCF-7 (132.7 [Formula: see text] 42.6 kBq/mL). [²²⁵Ac]Ac-Macropa-matuzumab demonstrated favourable biodistribution and was cleared from most non-target organs by day-10 p.i. 57% of mice bearing MDA-MB-468 xenograft treated with [²²⁵Ac]Ac-Macropa-matuzumab had complete remission (CR). Less pronounced effect was observed for MDA-MB-231 xenograft.

Conclusion: [²²⁵Ac]Ac-Macropa-matuzumab was safe and effective against EGFR-positive TNBC.

The majority of publicly available genomics data originates from populations of European ancestry. This limits understanding and detection of inherited genetic risk factors for breast cancer in other populations. To assess the extent to which deficits in knowledge of the genetics of breast cancer risk exist for populations of non-European ancestry, we compared data available on putative breast cancer risk variants in the ClinVar database for populations of different ancestry. Protein-coding insertions and deletions (indels) and single-nucleotide polymorphisms (SNPs) private to populations of Non-Finnish European (NFE), African (AFR), Admixed American (AMR), East Asian (EAS) and South Asian (SAS) ancestry from the Genome Aggregation Consortium (gnomAD v4) were identified for nine established breast cancer risk genes. The percentage of private protein-coding variants listed as 'Unreported' by gnomAD in ClinVar were compared between populations. The SAS population had the biggest knowledge deficit, as 43.4% of private SAS variants were not reported in ClinVar, compared to 20-30% for other populations. Proportionally fewer SAS variants were reported for all 9 genes, with the difference reaching an adjusted p < 0.05 for PALB2, ATM and BRCA2 when compared to NFE. In contrast, few genes had significantly lower ClinVar reporting rates for AFR, AMR and EAS than for NFE. ClinVar reporting deficits in the SAS population were observed for both missense and protein-truncating variants. Unreported variants were usually very rare and largely absent in other public repositories. A substantial fraction of unreported variants were protein-truncating (17.2%), or missense with high predicted pathogenicity scores, representing novel candidate breast cancer risk alleles. Our work demonstrates putative breast cancer risk variants from populations of South Asian ancestry are less likely to be reported in ClinVar. Defining and removing barriers to reporting potential risk variants for breast cancer from South Asian populations is needed to reduce this knowledge deficit.

Background: Metastatic disease is the main cause of breast cancer (BC)-related deaths, but prediction of metastases remains challenging especially in the large and diverse group with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors. Molecular tumor features beyond currently used markers could provide important information for stratifying metastatic risk. To allow for the discovery of new subtypes and molecular tumor features associated with metastatic spread, i.e., both lymph node and distant metastases, we here leverage advances in proteomic profiling of tumors.

Methods: We developed a protocol for proteome and phosphoproteome analysis using label-free data independent acquisition (DIA) liquid chromatography tandem mass spectrometry (LC-MS/MS) and integrated the generated data with parallel transcriptome data for the profiling of 182 ER-positive, HER2-negative primary BC tumors from the SCAN-B cohort.

Results: A total of 13,571 protein groups, 7107 phosphopeptides and 13,085 expressed genes were quantified in at least 70% of the samples. The data showed clear differences between invasive lobular carcinoma and no special type cancers, including the hallmark loss of E-cadherin expression and differences in catenin levels. We identified potential new subtypes with differential immune infiltration patterns and survival through unsupervised consensus clustering. Additionally, by adopting an integrative, multiomic data analysis workflow, we identified several potential protein markers of both lymph node and distant metastases. For lymph node metastasis, the level of phosphorylated ES8L2 serine at position 570 (multivariable p value = 0.05, HR = 0.61, 95% CI 0.38-0.99) was associated with improved recurrence-free survival, and showed decreased abundance in lymph node positive cases. For distant metastases, on the other hand, proteins belonging to the heat shock protein 90 family were associated with worse distant recurrence-free survival (multivariable p value = 0.0058, HR = 2.10, 95% CI 1.24-3.55), with significantly higher abundance levels in patients with a distant recurrence event. These correlations with survival could also be validated in multiple external cohorts.

Conclusions: In summary, we present the most comprehensive matched multiomic dataset from ER-positive/HER2-negative BC tumors, not only serving as an invaluable resource for further advancing precision medicine but also allowing the discovery of potential biomarkers and providing unique insights into metastatic processes.

Trial registration: Sweden Cancerome Analysis Network-Breast: Genomic Profiling of Breast Cancer (SCAN-B), beginning 2010-08, NCT02306096.