PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced ...BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8
T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
Research on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis ...and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival.
13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors).
Mean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality.
High fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes.
Significance Triple negative breast cancers (TNBCs) have a poor prognosis (5-y survival of 74.5%) among all breast cancer patients (5-y survival of greater than 95%) because of the aggressiveness of ...the disease and the lack of targeted therapeutics. We show that intercellular adhesion molecule-1 (ICAM-1) is differentially expressed in human TNBC tumor tissues by immunohistochemistry and in human TNBC cell lines via quantification of gene and protein expression. Iron oxide nanoparticles functionalized with ICAM-1 antibody (ICAM-IONP) were synthesized as MRI probes. An in vivo signal enhancement of 2.6-fold for ICAM-IONPs was measured relative to controls, demonstrating that ICAM-1 is a potential diagnostic and therapeutic target for TNBC treatment.
Triple negative breast cancers (TNBCs) have a high mortality rate owing to aggressive proliferation and metastasis and a lack of effective therapeutic options. Herein, we describe the overexpression of intercellular adhesion molecule-1 (ICAM-1) in human TNBC cell lines and tissues, and demonstrate that ICAM-1 is a potential molecular target and biomarker for TNBC therapy and diagnosis. We synthesized ICAM-1 antibody-conjugated iron oxide nanoparticles (ICAM-IONPs) as a magnetic resonance imaging (MRI) probe to evaluate tumor targeting. Quantitative analysis of ICAM-1 surface expression predicted the targeting capability of ICAM-IONPs to TNBC cells. MRI of the TNBC xenograft tumor after systemic administration of ICAM-IONPs, coupled with iron quantification and histology, demonstrated a significant and sustained MRI contrast enhancement and probe accumulation in tumors with ICAM-1 overexpression relative to control. Identification of ICAM-1 as a TNBC target and biomarker may lead to the development of a new strategy and platform for addressing a critical gap in TNBC patient care.
Significance This study is the first demonstration, to our knowledge, of the application of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for discrimination of breast cancer ...and delineation of tumor margins. Using DESI-MSI, it is possible to discriminate between cancerous and adjacent normal tissue on the basis of the detection and specific spatial distributions of different lipid species. This study proves the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. It will allow the surgeon to access to this information in real time so as to make accurate intraoperative decisions quickly. It will result in improved cosmesis and decrease the need for multiple operations for margin reexcision.
Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant ...fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
The breast is a dynamic organ whose response to physiological and pathophysiological conditions alters its disease susceptibility, yet the specific effects of these clinical variables on cell state ...remain poorly annotated. We present a unified, high-resolution breast atlas by integrating single-cell RNA-seq, mass cytometry, and cyclic immunofluorescence, encompassing a myriad of states. We define cell subtypes within the alveolar, hormone-sensing, and basal epithelial lineages, delineating associations of several subtypes with cancer risk factors, including age, parity, and BRCA2 germline mutation. Of particular interest is a subset of alveolar cells termed basal-luminal (BL) cells, which exhibit poor transcriptional lineage fidelity, accumulate with age, and carry a gene signature associated with basal-like breast cancer. We further utilize a medium-depletion approach to identify molecular factors regulating cell-subtype proportion in organoids. Together, these data are a rich resource to elucidate diverse mammary cell states.
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•Multimodal single-cell analyses identify breast epithelial and stromal subtypes•Spatially distinct epithelial subsets are linked with age, parity, and BRCA2 status•Alveolar cells with poor transcriptional lineage fidelity accumulate with age•Subtypes of the three major epithelial lineages are maintained in organoid cultures
Gray, Li, Rosenbluth, Selfors et al. generate a multi-dimensional atlas of breast tissues and organoids. Distinct epithelial subtypes are found to be associated with age, parity, and BRCA2 mutation. An alveolar subset termed basal-luminal cells displays poor transcriptional lineage fidelity and gene expression signatures associated with aggressive basal-like breast cancers.
Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is ...overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.
•Cyclin D1/CDK4 mediate resistance to HER2 blockade in HER2+ breast cancer•CDK4/6 inhibition suppresses mTORC1, relieving inhibition of EGFR family kinases•Combined CDK4/6 and HER2 inhibition is effective in transgenic and PDX mouse models•CDK4/6 inhibitors delay tumor recurrence in a transgenic HER2+ breast cancer model
Goel et al. show that cyclin D1/CDK4 mediate targeted therapy resistance in HER2+ breast cancer. CDK4/6 inhibition overcomes this resistance by increasing tumor cell dependence on EGFR family kinase signaling. CDK4/6 inhibitors resensitize PDX tumors to HER2-targeted therapies and delay tumor recurrence in vivo.
Abstract
Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16
INK4A
is deficient in the majority ...of HER2+ BCBMs. p16
INK4A
-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM.
Objectives.
Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with high mortality and poor response to treatment. A significant fraction of SDCs are HER2 positive. This retrospective ...review examines HER2 testing in SDC and the outcome of trastuzumab‐based therapy in adjuvant and palliative settings.
Methods.
A total of 13 patients with SDC and HER2/neu expression by immunohistochemistry of 1–3+ were treated with trastuzumab in adjuvant (n = 8) or palliative (n = 5) setting. Adjuvant therapy consisted of concurrent radiation and chemotherapy with weekly paclitaxel, carboplatin, and trastuzumab (TCH) for 6 weeks followed by TCH for 12 weeks and trastuzumab alone for 1 year. Palliative treatment for metastatic disease consisted of TCH every 3 weeks for 6 cycles followed by trastuzumab for variable time periods with or without second‐line chemotherapy for progression. All patients had fluorescence in situ hybridization testing for HER2/neu gene amplification.
Results.
The median duration of follow‐up was 27 months (range: 8–48 months). In all, 62% of adjuvant patients (5/8) had no evidence of disease more than 2 years from completion of therapy. All patients with metastatic disease (5/5 patients) responded to treatment with TCH. One patient achieved a complete response and remains with no evidence of disease 52 months after initiation of TCH. The median duration of response was 18 months (range: 8–52 months).
Conclusion.
HER2/neu positivity and treatment with trastuzumab correlated well with long‐term survival and response in our patients. Based on this data, we propose that HER2/neu status be examined routinely in all patients with SDCs and the treatment be directed accordingly.
摘要
目的. 涎腺导管癌（ SDC）是一种罕见的侵袭性恶性肿瘤，死亡率高，对治疗的应答很差。相当一部分SDC为HER2阳性。本篇回顾性综述探讨了SDC中的HER2检测情况，以及以曲妥珠单抗为基础的方案作为辅助治疗与姑息治疗患者的临床结局。
方法. 总计13例免疫组化检测HER2/neu表达为+ ~ +++的SDC患者接受了曲妥珠单抗辅助治疗（n = 8）或姑息治疗（n =5）。辅助治疗包括同步放疗与每周一次紫杉醇、卡铂和曲妥珠单抗组成的化疗方案（TCH）治疗6周，继以TCH治疗12周，曲妥珠单抗单药治疗1年。对转移性疾病的姑息治疗包括每3周一次TCH，共6个周期，继以曲妥珠单抗（疗程未定）联合或不联合二线化疗（针对疾病进展）。所有患者均通过荧光原位杂交检测HER2/neu基因扩增。
结果. 中位随访时间为27个月（范围：8 ~48个月）。总体上，接受辅助治疗的患者中有62%（5/8）在完成治疗后超过2年的时间内未出现疾病征象。所有转移性疾病患者（5/5）对TCH治疗应答。1例患者获得完全缓解，并在TCH开始治疗52个月后保持无病状态。中位缓解持续时间为18个月（范围：8~ 52个月）。
结论. HER2/neu阳性和应用曲妥珠单抗治疗与患者长期生存和缓解的相关性良好。基于以上数据，本研究建议所有SDC患者应常规检查HER2/neu状态，以便进行更有针对性的治疗。
Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with high mortality and poor response to treatment. This retrospective study found that HER2/neu positivity and treatment with trastuzumab correlated well with long‐term survival and response in adjuvant and palliative settings.
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