Brain metastases (BM) are frequent in small cell lung cancer (SCLC). Novel insights into their pathobiology are needed for development of better therapies. We investigated tumor-infiltrating ...lymphocyte (TIL) subsets (CD3+, CD8+, CD45RO+, FOXP3+ and PD-1+) and expression of PD-L1 in a series of 32 SCLC BM specimens and four matched primary tumor specimens using immunohistochemistry. 30/32 (93.8 %) BM specimens showed TIL infiltration. CD3+ TILs were observed in 30/32 (93.8 %) BM specimens, CD8+ TILs in 25/32 (78.1 %), CD45RO+ TILs in 15/32 (46.9 %), FOXP3+ TILs in 15/32 (46.9 %) and PD-1+ TILs in 1/32 (3.1 %) BM specimens. Patients with infiltration of CD45RO+ TILS had a significantly longer median survival time (11 months; 95 % CI 0.000–26.148) as compared to patients without the presence of CD45RO+ TILs (5 months; 95 % CI 0.966–9.034; p = 0.007; log rank test). Membranous PD-L1 on tumor cells was observed in 24/32 (75.0 %) BM specimens, with 11/32 (34.4 %) cases showing PD-L1 expression in over 5 % of viable BM tumor cells. PD-L1 expression on TILs was seen in 8/32 (25.0 %) and on tumor infiltrating macrophages in 9/32 (28.1 %) cases. Patients with PD-L1 expression on TILs presented with improved survival prognosis (6 versus 29 months; p = 0.002; log rank test). Among matched primary tumors, all (4/4; 100 %) specimens showed TIL infiltration, while PD-L1 expression found in only 1/4 (25.0 %) specimen. TIL infiltration and PD-L1 expression are commonly found in SCLC BM and presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seem to associate with favorable survival times. Our data suggest an active immune microenvironment in SCLC BM that may be targetable by immune-modulating drugs.
Landmark studies have established trastuzumab in the treatment of HER2-positive breast cancer. The present systematic review and meta-analysis aims to synthesize all available data, so as to evaluate ...the safety of trastuzumab during pregnancy. This study was performed in accordance with the PRISMA guidelines. All studies that examined the safety of trastuzumab administered during pregnancy, regardless of sample size, were considered eligible. Overall, 17 studies (18 pregnancies; 19 newborns) were included. In 55.6 % of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration was 14.8 weeks. Occurrence of oligohydramnios/anhydramnios (O/A) was the most common (61.1 %) adverse event. 73.3 % of pregnancies exposed to trastuzumab during the second/third trimester were complicated with O/A; the respective rate of pregnancies exposed to trastuzumab exclusively during the first trimester was 0 % (
P
= 0.043). The mean GA at delivery was 33.8 weeks, and the mean weight of babies at delivery was 2,261 gr. In 52.6 % of cases, a healthy neonate was born. At the long-term evaluation, all children without problems at birth were healthy with a median follow-up of 9 months, while four out of nine children facing troubles at birth were dead within an interval ranging between birth and 5.25 months. All children exposed to trastuzumab in utero exclusively in the first trimester were completely healthy at birth. Trastuzumab should not be administered during pregnancy. However, for women who become accidentally pregnant during trastuzumab administration and wish to continue pregnancy, trastuzumab should be stopped and pregnancy could be allowed to continue.
Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity ...(ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.
We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.
The prognosis of patients with HER2-positive breast cancer was dramatically changed by the introduction of targeted therapies. With trastuzumab, pertuzumab, and T-DM1 widely used as (neo)adjuvant ...therapy today, novel treatment options are required to optimize treatment of HER2-positive metastatic disease. Trastuzumab-deruxtecan is an antibody-drug conjugate (ADC) consisting of a monoclonal humanized immunoglobulin G1 antibody, a linker molecule, and the exatecan derivative DXd. T-DXd has a higher drug to antibody ratio compared with T-DM1; in addition, membrane permeability of DXd is high, resulting in an increased bystander effect. Results from early clinical development suggest a clinically relevant activity of T-DXd in heavily pretreated patients with HER2-positive metastatic breast cancer progressing on T-DM1. Interstitial lung disease was a side-effect requiring special attention and was observed in approximately 13% of patients.
This article reviews preclinical and clinical data on T-DXd. A systematic literature search was performed to identify relevant publications. The search included original research articles, abstracts from major conferences, and reviews and was limited to English-language publications.
T-DXd is an efficacious and tolerable drug and harbors promise as a key addition to the therapeutic field in HER2-positive breast cancer.
Purpose IMpassion130 led to the approval of atezolizumab plus nab-paclitaxel as first-line treatment for patients with unresectable locally advanced or metastatic triple-negative, PD-L1 immune-cell ...positive breast cancer (BC) by the European Medicines Agency (EMA). The objective of the present study was to investigate the implementation, safety and efficacy of this combination in the initial phase after approval. Methods A retrospective data analysis including all BC patients who received atezolizumab and nab-paclitaxel between 1.1.2019 and 31.10.2020 at the Department of Obstetrics and Gynecology and the Department of Medicine 1, respectively, at the Medical University of Vienna, Austria, was performed. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Maier product-limit method. Owing to the retrospective nature of this study, all statistics must be considered exploratory. Results In total 20 patients were included in the study. Median follow-up was 7.1 months (IQR 5.2-9.1). Median PFS was 3.0 months (SE = .24; 95% CI 2.5; 3.5). Median OS was 8.94 months (SE = 2.34, 95%CI 4.35; 13.53). No new safety signals were observed. Conclusion The present study showed a considerably shorter PFS (3.0 vs. 7.5 months) and OS (8.94 vs. 25.0 months) than IMpassion130 putatively owing to the use of atezolizumab in later treatment lines, more aggressive tumors and a study population with higher morbidity compared to the pivotal trial. Keywords: Breast cancer, Atezolizumab, Real-world, Progression-free survival, Overall survival
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diffusion‐weighted MRI (DWI) provides insights into tissue microstructure by visualization and quantification of water diffusivity.
Quantitative evaluation of the apparent diffusion coefficient (ADC) ...obtained from DWI has been proven helpful for differentiating between malignant and benign breast lesions, for cancer subtyping in breast cancer patients, and for prediction of response to neoadjuvant chemotherapy. However, to further establish DWI of breast lesions it is important to evaluate the quantitative imaging biomarker (QIB) characteristics of reproducibility, repeatability, and diagnostic accuracy.
In this intra‐individual prospective clinical study 40 consecutive patients with suspicious findings, scheduled for biopsy, underwent an identical 3T breast MRI protocol of the breast on two consecutive days (>24 h). Mean ADC of target lesions was assessed (two independent readers) in four separate sessions. Reproducibility, repeatability, and diagnostic accuracy between examinations (E1, E2), readers (R1, R2), and measurements (M1, M2) were assessed with intraclass correlation coefficients (ICCs), coefficients of variation (CVs), Bland–Altman plots, and receiver operating characteristic (ROC) analysis with calculation of the area under the ROC curve (AUC). The standard of reference was either histopathology (n = 38) or imaging follow‐up of up to 24 months (n = 2).
Eighty breast MRI examinations (median E1–E2, 2 ± 1.7 days, 95% confidence interval (CI) 1–2 days, range 1–11 days) in 40 patients (mean age 56, standard deviation (SD) ±14) were evaluated. In 55 target lesions (mean size 25.2 ± 20.8 (SD) mm, range 6–106 mm), mean ADC values were significantly (P < 0.0001) higher in benign (1.38, 95% CI 1.27–1.49 × 10−3 mm2/s) compared with malignant (0.86, 95% CI 0.81–0.91 × 10−3 mm2/s) lesions. Reproducibility and repeatability showed high agreement for repeated examinations, readers, and measurements (all ICCs >0.9, CVs 3.2–8%), indicating little variation. Bland–Altman plots demonstrated no systematic differences, and diagnostic accuracy was not significantly different in the two repeated examinations (all ROC curves >0.91, P > 0.05).
High reproducibility, repeatability, and diagnostic accuracy of DWI provide reliable characteristics for its use as a potential QIB, to further improve breast lesion detection, characterization, and treatment monitoring of breast lesions.
In an intra‐individual clinical study the quantitative imaging biomarker characteristics for DWI of breast lesions were evaluated. Both reproducibility and repeatability demonstrated an almost perfect agreement (all intraclass correlation coefficient values >0.9) with little variation (all coefficients of variation 3.2–8%). Diagnostic accuracy showed no significant difference in two repeated identical examinations (all ROC curves >0.91, P > 0.05). Consequently, DWI of breast lesions provides reliable characteristics for use as a potential quantitative imaging biomarker, to further improve breast lesion detection, characterization, and treatment monitoring.
Background Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel ...approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial. Methods Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells. Results Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase. Conclusion The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer. Keywords: Neoadjuvant chemotherapy, Breast cancer, Immune cells, Epirubicin, Docetaxel, Immunomodulatory markers, Prediction of response to chemotherapy
The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted ...therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.
Summary
The 2023 annual meeting of the American Society of Clinical Oncology (ASCO) was again held in June 2023 in Chicago. While not immediately practice changing, results from several interesting ...studies in the field of breast cancer (BC) were reported. In the phase III NATALEE trial, the addition of 3 years of ribociclib to standard adjuvant endocrine therapy resulted in a significant improvement in invasive disease-free survival (iDFS), making this the second positive study of CDK4/6 inhibitors in the adjuvant setting. A subgroup analysis from the MONARCHe trial indicated sustained benefit of adjuvant abemaciclib in the subset of patients with low dose intensity. Long-term outcome of the neoadjuvant phase II PHERgain trial indicated excellent iDFS results in patients receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy based upon PET metabolic response as a dynamic biomarker. In a biomarker analysis from the SOFT trial, more high-risk tumors were observed in the very young patient subset, while the PAM50 risk-of-recurrence score was not predictive for benefit of ovarian function suppression. A large retrospective analysis evaluated the role of adjuvant chemotherapy in small, node-negative triple-negative breast cancer. A clear benefit for chemotherapy was only seen in tumors > 10 mm of size. In metastatic HR-positive breast cancer, the PALMIRA trial with palbociclib beyond progression yielded negative results. An update from the PADA-1 trial again indicates the promising role of repeated liquid biopsies for treatment guidance in metastatic disease. Patritumab deruxtecan, a HER3-directed antibody–drug conjugate yielded promising response rates in HER2-negative metastatic breast cancer patients. In addition, several retrospective analyses focused on the important question of treatment sequencing.
Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early ...triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC.
We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate.
To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate.
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