bluuebunny/crossref_metadata_2025 huggingface dataset:
FcεRIγ-negative NK cells and association with improved outcomes in trastuzumab-treated patients.
Authors: Perez Vincent Michael , Selitsky Sara R. , Yao Bin , Bigley Austin , Kim Sungjin , Frohlich Mark Walter
Published: June 2023

e12538

Background: A subset of natural killer cells lacking FcεRIγ expression (g-NK cells) demonstrate enhanced expansion, cytokine production, antibody-dependent cytotoxicity, and enhanced efficacy of therapeutic antibodies in preclinical models (Bigley, Blood Advances 2021). The monoclonal antibody, trastuzumab, is standard of care for treatment of HER2+ breast cancer in adjuvant and metastatic settings. We sought to determine whether the abundance of g-NK cells is associated with improved outcomes in trastuzumab-treated patients. Methods: We identified g-NK cells in single-cell (scRNA-seq) datasets from melanoma (n=47), renal (n=8), breast (n=29), and lung cancer (n=36) samples using predefined markers and defined a g-NK gene signature. We split the scRNA-seq cohorts into training and test sets and estimated cell-type compositions in pseudo bulk using MuSiC bulk tissue deconvolution (Wang, Nature Communications, 2019). We deconvoluted g-NK cells in 8 bulk RNA-seq HER2+ breast cancer cohorts (Table 1) and used Cox proportional hazard models to assess clinical outcomes stratified by g-NK and trastuzumab status. We reproduced our findings using real-world cohorts from patients sequenced via the Tempus xT test (Table 1). Results: The Spearman’s correlation coefficient between true and estimated pseudo bulk proportion of g-NK cells was 0.71 (p≤0.05). In a meta-analysis, the abundance of g-NK cells was associated with a lower hazard ratio (HR) for overall survival (OS) in trastuzumab-treated patients (cohorts 1-4; HR = 0.61; 95% CI, 0.37-0.99; p=0.04) but not trastuzumab-naive patients (cohorts 5-8; HR = 0.96; 95% CI, 0.80-1.15; p=0.65). In real-world, HER2+ breast cancer cohorts treated with trastuzumab, higher real-world progression-free survival (rwPFS) was associated with abundance of g-NK cells (N=104, HR = 0.78; 95% CI, 0.64-0.96; p=0.02). A similar trend was observed in real-world trastuzumab-treated gastric cancer patients (N=79, HR = 0.85; 95% CI, 0.72-1.00; p=0.06). Conclusions: G-NK cells are associated with improved OS and PFS in trastuzumab-treated patients from both clinical trials and real-world datasets, suggesting their presence may serve as a predictive marker for treatment efficacy. Adoptive transfer of g-NK cells is being explored to augment the efficacy of therapeutic monoclonal antibodies. [Table: see text]
Simultaneous expression of androgen receptor and tumor-associated neutrophil in breast cancer subtypes.
Authors: Moghimi Minoosh , Vadoudi Shahin , Amirian Majid , Ahmadi Farzane , Amirian Mohammad Borna , Khodadadi Kasra , Mansouri Reza
Published: June 2023

e12539

Background: Considering the heterogeneity of breast cancer phenotypes and different response rates to treatment, it is essential to determine prognostic markers that could confer therapeutic role as well. In this study, androgen receptor (AR) and tumor-associated neutrophil (TAN) in female breast cancer were investigated and their coherency with different subtypes of breastcancer and pathology findings were assessed. Methods: This cross-sectional study was conducted on patients with Stage I-IV breast cancer who were referred to Borna Pathology Center in Zanjan, Iran during 2018-2021. The tumoral paraffine blocks were evaluated for AR (by the IHC method) and TAN (by morphology and the IHC staining for myeloperoxidase). Relationships in different subtypes and stages were assessed.Using univariate logistic regression between 5 subtypes (defended by ER, PR, HER2, and Ki67), stage, age, metastasis (M), and grade with AR and TAN were studied separately and simultaneously. Results: We collected data from 83 women with Stage I-IV breast cancer with mean ± SD age of diagnosis 49.3±11.2 years. Percentage of AR+, TAN+, and AR+&TAN+ were 71.1, 43.4, and26.5, respectively. The frequency of AR+ and AR-&TAN- was high in hormone-positive subtypes, while TAN+ was frequent in the triple-negative group and AR+&TAN+ in Luminal A and B groups. The relation between age, M, and Stage with AR, TAN, and AR & TAN was not significant. AR was significantly related to subtype and grade. Conclusions: AR+ probability was significantly lower in Triple Negative subtype and poorly differentiated grade. Based on the heterogeneity of the presentation of these markers, survival evaluation can be important in risk assessment of them. Relationship between AR, TAN, and AR&TAN with study variables. [Table: see text]
Neutrophil/lymphocyte ratio (NLR) and albumin-globulin ratio (AGR): Correlations with outcomes in patients with stage I-III breast cancer.
Authors: Tey Min Li , Zhou Siqin , Nitar Phyu , Mohd Ishak Hanis Mariyah , Yang Christina Shi-Hui , Kusumawidjaja Grace , Chay Wen Yee , Wong Fuh-Yong , Wong Ru Xin
Published: June 2023

e12548

Background: The ratios of blood-based inflammatory biomarkers, such as NLR and AGR, have been found to correlate with outcomes in various malignancies. Higher NLR values reflect a pro-inflammatory state and are generally associated with worse outcomes. Conversely, higher AGR values reflect a fitter nutritional status and/or less chronic inflammation, and may hence be associated with better outcomes. We aim to investigate the association between NLR and AGR with survival among stage I-III breast cancer patients treated curatively, and with pathological complete response (pCR) rates among patients who have undergone neoadjuvant chemotherapy (NACT). Methods: A retrospective study of stage I-III breast cancer patients treated in a healthcare cluster in Singapore from 2011-2017 was performed. Clinical data was extracted from a prospectively maintained registry alongside full blood count (FBC) and liver function test (LFT) results. FBC and LFT were performed either 1-month pre-chemotherapy or pre-operatively. pCR is defined as stage ypT0/isN0M0 among patients who have undergone NACT. Optimal cut-offs for the NLR and AGR values are determined by maximal Youden’s Index for pCR, DFS and OS. Multivariate logistic regression, with NLR, AGR, age, stage, grade, and subtype, was used, with survival data between groups compared using the Cox regression analysis and log-rank tests. Results: A total of 1,188 patients were included in our study, with 323 patients receiving NACT, and 865 patients undergoing upfront surgery. On multivariable analysis of patients treated with NACT, higher AGR was associated with higher pCR (cutoff >1.3, HR 2.0, p=0.02) and better DFS (>1.6, HR 0.4, p=0.02) while a higher NLR with worse DFS (>4.1, HR 1.8, p=0.03). In upfront surgery patients, higher AGR was associated with better OS (cutoff >1.2, HR 0.5, p=0.00) while a higher NLR predicted for worse OS (>2.4, HR 1.6, p=0.02). Conclusions: Inflammatory markers may be useful in predicting response to NACT and prognosticating survival. Larger studies should be undertaken to explore their value in clinical decision making. [Table: see text]
Correlation between Magee score and recurrence score in Indian patients with breast cancer.
Authors: Davis Sissmol , John Dr Serene Sara , Santoki Aditya , Sankaranarayanan Sreedharan , Keechilat Pavithran , Thampy Cherian , Shivashankara Yashaswini , Thomas Boben , Baghmar Saphalta , Rajendranath Rejiv , Warrier Narayanankutty Edavalath , Mathew Aju
Published: June 2023

e12555

Background: Recurrence score (RS) from Oncotype Dx (ODx) test predict chemotherapy benefit in estrogen receptor (ER) positive, and HER2-negative patients with breast cancer. ODx is an expensive test in an Indian practice setting - cost of adjuvant chemotherapy is one-sixth of the cost of the test. Magee equations use histopathological variables, and semiquantitative results from ER, PR and Ki-67, to calculate Magee score (MS) and provide a cost-effective surrogate mechanism for predicting RS. We aimed to assess the correlation between MS and RS in an Indian setting. Methods: Pathology reports were obtained from oncologists in India. Immunohistochemistry for ER and PR were reported using the Allred system. Therefore, two methods were identified to estimate H-scores - using a calculated method (A), and using an expert-approximated (B) method. MS were calculated by a single investigator blinded to the RS. MS and RS were then assessed for correlation via the Pearson correlation method. MS were arbitrarily stratified into ≤ 15, 15 - 30, and ≥ 30, and their overall agreement (OA) or concordance with RS risk categories, ≤ 15, 15 - 30, and ≥ 30, were assessed. The OA was assessed by determining the proportion of patients in similar risk categories across low, intermediate and high-risk RS and MS. Results: Among 34 patients included in the study, 38% (13) had an RS ≤ 15, 38% (13) had an RS between 15 and 30, and 23% (8) had an RS ≥ 30. Correlation coefficient between MS and RS was 0.78 for both methods of estimation (p<0.0001). The OA between MS-A and RS, and MS-B and RS were 59% (20/34) and 47% (16/34) respectively. The concordance between low-risk MS-A and RS is 78% (n=9) and between low-risk MS-B and RS is 50% (n=20). The concordance between high-risk MS-A and RS is 100% (n=2) and high-risk MS-B and RS is 100% (n=2). Conclusions: Although there is good correlation between RS and MS, the concordance between the two in similar risk categories is not optimal. Of the two methods to estimate H-score from Allred score, the calculated method seems to be more optimal. Our pilot study shows good correlation between MS and RS. We recommend that pathologists incorporate H-score as part of the reporting of ER and PR. A larger prospective study will be useful to test our hypothesis for the use of MS as a predictive tool for adjuvant chemotherapy in breast cancer.
Use of the genetic signature of 70-genes MammaPrint in comparision with the immunohistochemical profile to de-escalate systemic treatment in the elderly population: Real-world study (AGEMA-BR).
Authors: Mansani Fabio , Freitas-Junior Ruffo
Published: June 2023

e12561

Background: the elderly population, generally, presents a lower performance and greater susceptibility to complications and adverse effects of therapies, inferring that the de-escalation of cytotoxic therapies is desirable. Genetic signatures, including MammaPrint/ BluePrint, are the most appropriate tools to select among estrogen receptor (ER) patients with high clinical risk, who could, with oncological safety, not receiving adjuvant chemotherapy. Objective – to evaluate the performance of MammaPrint™ (MP) / BluePrint (BP) and the immunohistochemical profile (IHC) in the de-escalation of systemic therapy in the elderly population with breast cancer and Luminal profile. Methods: from the patients in the AGEMA-BRA study, which analyzes the performance of the 70-gene MammaPrint™ platform in the Brazilian population, those aged 70 years or older, with high clinical risk, who had data on the immunohistochemical profile available (37 patients). A comparative analysis was performed between the genomic profile (Luminal A/B on BluePrint; high and low risk on MammaPrint™ and the immunohistochemical profile (considered Luminal A with ER >10%, RP>10%, HER2 negative, Ki67 ≤20% Luminal B with ER>10%, HER2 negative, Ki67>20%) and clinical endpoints including disease-free survival (DFS) and overall survival (OS). Data analysis used accuracy and the Kappa coefficient (considering concordance >0, 6). Results: mean age at diagnosis 73.1 years (70–80 years) and mean follow-up (FU) of 42 months. Of the 15 patients with high risk / luminal B by MP / BP, 5 were classified as luminal A by the IHC profile with a disagreement of 33.33%; of the 22 low-risk / luminal A patients by MP/BP, 6 were classified as luminal B by the IHC, a disagreement of 27.27%. Statistical analysis showed an accuracy between the IHC profile and the MP of 70.27%. The use of the IHC profile, when compared with the MP/BP, showed a sensitivity of 66.7% and a specificity of 72.7%. Of the 14 patients at high risk due to MP, 2 did not undergo chemotherapy treatment. All patients (at high and low risk) received adjuvant endocrine therapy with an aromatase inhibitor. After 42 months of medium FU, all patients were alive and disease-free, inferring DFS and OS of 100%. Conclusions: the analysis of data and outcomes in the elderly population of the AGEMA-BRA study with high clinical risk, demonstrated limited accuracy and low agreement in the stratification into high and low risk between the profile by IHC and the MP/BP. The use of the genomic platform may have been relevant in risk stratification and outcomes in this population. Studies with a larger sample and longer FU are needed to confirm the usefulness of genetic signatures in the de-escalation of systemic treatment in the elderly population with high clinical risk.
Clinical and biological heterogeneity in triple-negative breast cancer and HER2-low.
Authors: Hu Xi'e , Yang Ping , Chen Songhao , Wei Gang , Yuan Lijuan , Yang Zhenyu , Yang Lin , Peng Shujia , Dong Yanming , He Xianli , Bao Guoqiang
Published: June 2023

e12565

Background: HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear. Methods: We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2low) and 94 HER2-negtive (HER2neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2neg vs. HER2low, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples. Results: Compared with HER2neg TNBC, HER2low TNBC patients exhibited malignant clinical features with larger tumor size ( P = 0.04), more lymph nodes involvement ( P = 0.02), higher histological grade of lesions ( P < 0.001), higher Ki67 status ( P < 0.01), and a worse prognosis ( P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2low TNBC but not in HER2neg TNBC patients. scRNA-seq revealed that HER2low TNBC which showed more metabolically active and aggressive hallmarks, while HER2neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes ( IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2low and HER2neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2neg TNBC revealed a potentially more active immune microenvironment than HER2low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8+ effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response. Conclusions: This study suggests that HER2low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provides new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.
Use of tumoral LDH to predict residual tumor burden after neoadjuvant chemotherapy in breast cancer.
Authors: Lee Soo Jung , Lee In Hee , Kang Byeongju , Park Jee-Young Nora , Lee Jeeyeon , Park Ho Yong , Park Ji-young , Chae Yee Soo
Published: June 2023

e12566

Background: The Residual Cancer Burden (RCB) score has been validated as an independent prognostic factor in all subtype of breast cancer after neoadjuvant chemotherapy (NAC). Early prediction of NAC response enable better stratification for selecting chemotherapy. Glucose metabolism in cancer cells produces various glycolytic metabolites which are related to breast cancer prognosis. In this study, we evaluated the association of glucose transporters and enzymes involved in glucose metabolism with clinic-pathological factors for early prediction of NAC response. Methods: RCB scores were retrospectively evaluated from patients with stage I-III breast cancer treated with neoadjuvant chemotherapy. We selected 7 target transporters and enzymes [GLUT1, hexokinase 2 (HK2), lactate dehydrogenase (LDH), MCT1, MCT4, IGF1RA, and IGF1RB] involved in glucose metabolism and evaluated in relationships with pretreatment clinical/pathological characteristics and treatment outcomes including RCB. Results: 236 breast cancer patients who underwent NAC followed by surgery between 2010 and 2016 in Kyungpook National University Chilgok Hospital were included. Among them, 145 (61.4%), 44 (18.6%), and 47 (19.9%) were luminal, HER2-enriched, and TNBC subtypes. RCB 0 was determined 50 (21.2%), 35 (14.8%) RCB I, 91 (38.6%) RCB II and 60 (25.4%) RCB III. After a median follow-up of 98 months, 60 (25.4%) relapses, 43 (18.2%) distant relapses, and 34 (14.4%) deaths were observed. RCB score was significantly associated with disease specific survival (DSS) and overall survival (OS). RCB III were significantly increased risk of relapse (HR=13.517, CI [1.809-101.010], P<0.001). The tumoral expression rates of the target molecules were 76.0, 31.1, 42.1, 54.9, 67.9, 78.4, and 49.8% for GLUT1, HK2, LDH, MCT1, MCT4, IGF1RA, and IGF1RB, respectively. Among them, LDH was significantly associated with RCB III (OR=4.533, P=0.014) and worse disease specific survival (HR=2.29 P=0.019). Conclusions: Tumoral expression of LDH could be considered as an independent biomarker in predicting high risk of relapse (RBC III) and survival in all subtype of breast cancer.
Treatment patterns and clinical outcomes of newly diagnosed early-stage and locally advanced triple negative breast cancer (TNBC): A retrospective cohort analysis of national real-world data in England.
Authors: Barham Manpreet , Ntais Dionysios , Macey Karen , Murray Kirsty , Castillo Catherine , Ford Alexander , Patel Amisha , Holbrook Tim
Published: June 2023

e12577

Background: TNBC patients have poorer survival outcomes when compared to other types of breast cancer, due to the lack of treatment options available and the aggressiveness of the disease. The current standard of care for early-stage TNBC is neoadjuvant pembrolizumab in combination with chemotherapy followed by pembrolizumab monotherapy after surgery (KEYNOTE-522), however prior to this treatment options and outcomes have been relatively limited compared to hormone receptor- and HER2- positive breast cancers. This study aimed to describe the treatment patterns and clinical outcomes of early-stage and locally advanced TNBC patients in England before the approval of KEYNOTE-522. Methods: In this retrospective cohort study, data from the English National Cancer Registration and Analysis Service databases (Cancer Registry, Systemic Anti-Cancer Therapy, Hospital Episode Statistics [HES], National Radiotherapy Dataset and Diagnostic Imaging Dataset) were used. Adults with a first record of primary early-stage or locally advanced TNBC (stage II – IIIb) between 01/01/2015 and 31/12/2018 were indexed. Treatment pathways and clinical outcomes were investigated over a maximum of 5-years follow-up period extending to December 2020. Outcomes were described descriptively. Results: A total of 3,475 patients met the inclusion criteria for the newly diagnosed TNBC cohort. 82.7% and 17.3% of patients were diagnosed at stage II and stage III respectively and, 83.3% were of white ethnicity, and 46.6% were node positive. Around 80% of patients had a primary surgery performed (i.e. a mastectomy or breast conserving surgery). Anthracyclines were the most common drug type used as a first regimen in both the neoadjuvant and adjuvant settings. During the follow up period, 37.7% and 15.3% of patients experienced locoregional or distant metastatic progression, respectively and 22.6% died. Median OS or EFS was not reached as < 50% patients died within the 5-year follow up period. The 5-year OS and EFS rate was ~57% and ~60%, respectively. Increased healthcare resource utilisation (HCRU) with associated high costs was reported in the time periods post diagnosis. The mean number of TNBC-related inpatient stays was the highest in the 3 to 6 months following index; 3.77 (SD = 3.95), costing a total of £4,992,150.48 (per patient cost: £1,458.84 [£1918.76], mean [SD]). Conclusions: This is the first real world evidence study using the England NCRAS datasets to assess the outcomes of the early-stage and locally advanced TNBC population in England. Treatment plans were heterogenous in TNBC patients and probability of survival was poor. This highlights the need for improvement of the treatment options and thus clinical outcomes of this patient population.
Reflex MammaPrint testing on breast core biopsies: A single center experience.
Authors: Kerrigan Colleen , Look Hong Nicole , Roberts Amanda , Nofech-Mozes Sharon , Jorden Tanya , Gandhi Sonal
Published: June 2023

e12581

Background: Breast cancer genomic assays are well established in the adjuvant setting, but still evolving in the neoadjuvant setting. Recent data shows that MammaPrint (MP)/BluePrint (BP) genomic assays in the neoadjuvant setting can reclassify hormone receptor positive (HR+), HER2 negative (HER2-) tumors into intrinsic phenotypes with corresponding responses to neoadjuvant therapy (NAC). We performed reflex MP/BP assays on invasive breast cancer core biopsies and evaluated the relationships between clinical risk, molecular risk and intrinsic phenotype. Methods: 150 consecutive HR+, HER2- invasive breast cancers were identified by core biopsy in a tertiary care cancer center and underwent reflex MP/BP testing by an external central laboratory between July 2021 and Jan 2022. Retrospective review was completed on patient demographics and tumor characteristics; descriptive statistics were performed. Results: Of 150 newly diagnosed HR+ HER2- breast cancers, 141 successfully had a reflex MP/BP test performed; 9 were not performed due to technical feasibility or clerical error. Of the 141 patients with a completed MP/BP assay, 7 had recurrent disease, and 8 had metastatic disease, these were excluded. Patients were categorized as clinically high (cHR) or low risk (cLR) using the criteria from the MINDACT trial and as molecularly high risk (MP HR) or low risk (MP LR) per their MP results. We then grouped patients with discordant clinical and molecular risk. We then examined clinical features and NAC receipt amongst these clinical and molecular risk groups. Conclusions: There was discordance between clinical and molecular risk in 38% of our cohort, 20% were cLR/MP and 18% were cHR/MP LR. The decision to give NAC was primarily driven by clinical risk as only 1 patient with cLR/MP HR received NAC. Amongst cHR/MP LR 87% did not get NAC, but this appears to have been a clinical decision as only 7 of these patients had a pre-operative oncology visit at which MP/BP was mentioned. Most (72%) of > cN1 patients received NAC, of the 5 who didn’t, 4 were in the MP LR group and had a pre-operative oncology visit where MP was mentioned. In this select group the genomic assay may have influenced the decision to withhold NAC. Reflex genomic assays for HR+ HER2- breast cancer may not be useful; the decision to integrate molecular risk into the decision for NAC is multifactorial and stage of disease may be most impactful. Further work is needed in this area. [Table: see text] [Table: see text]
Efficacy comparison of anthracycline and taxane when added to immune checkpoint inhibitor in neoadjuvant chemotherapy of triple negative breast cancer: Clinical evidence from size-reduction measurement by ultrasound.
Authors: Chen Shin-Cheh , Shen Shih-Che , Yu Chi-Chang , Chang Hsien-Kun , Lin Yung-Chang , Chen Jen-Shi , Lo Yun-Feng , Kuo Wen-Lin , Tsai Hsiu-Pei , Chou Hsu-Huan , Chu Chia-Hui , Shen Wen-Chi , Wu Ren-Chin , Ueng Shir-Hwa , Huang Yi-Ting
Published: June 2023

e12584

Background: Most chemotherapeutics can improve responses to immune checkpoint inhibitors (ICI) by increased immunogenicity. Anthracycline(AC), taxane(T) and platinum (CDDP) has most direct cytotoxic effect in neoadjuvant chemotherapy (NAC) of triple negative breast cancer (TNBC), but which one deserve the most immunostimulatory activity linked to their capacity of to kill cancer cell still unknown. Methods: A total of 91 patients with complete data of size measurement by ultrasound (US) were identified for the study from 363 consecutive TNBC patients received NAC between November 2010 to August 2022. They were divided into 3 groups. The 1st group patients received AC first, then T with CDDP, 2nd group in reverse sequence (T and CDDP first) and 3rd group, sequence as group 2 but adding ICI (pembrolizumab). Tumors size measured by US before chemotherapy, after 1st and after 2nd regimen of chemotherapy. Percentage of size reduction of tumor maximal diameter (cm), surface area (transverse x longitudinal diameter, cm2) and volume (measured by 1/6 p x transverse x longitudinal x height cm3) were calculated. Statistically significant was calculated using the Mann-Whitney U test for percentage of size reduction and Pearson's chi-squared test for pCR rate, p-value < 0.05 was considered significant. Results: There were 14, 56 and 21 patients in group 1, 2 and 3, respectively. The significant difference of pathologic complete response rates 7.1%, 44.6% and 76.2% in each group as shown. The volume, surface area and maximal tumor size reduction percentage after 1st regimen chemotherapy in group 1 (AC), group 2 (T+CDDP) and group 3 (ICI+T+CDDP) were -67.24, -55.43, -31.13; -85.45, -72.13, -45.61 and -87.13, -69.75, -45.02, respectively, and size reduction after 2nd regimen chemotherapy in group 2 (AC) were, -42.19, -30.19, -21.13; and group 3 (ICI+AC) were -77.78, -50.76, -30.65; respectively. A statistical non-significant trend of greater size reduction in ICI+ AC than AC alone was found. Conclusions: The study is the first, direct evidence demonstrated the synergistic effect of size reduction after NAC for TNBC with AC and ICI, but not T. It supports the potential benefit of combining chemotherapy with immunotherapy such as Tonic trial reported. [Table: see text]
Combined role of the neutrophil/lymphocyte ratio and Neo-Bioscore in neoadjuvant therapy in HER2-positive early breast cancer.
Authors: Sánchez Escudero Laura , Cobelas Cartagena Stephanie S , Morales Pancorbo David , Bayo Juan L.
Published: June 2023

e12613

Background: High neutrophil/lymphocyte ratio (NLR) is considered a poor prognostic factor in triple negative breast cancer but its role in HER2-positive early breast cancer (eHBC) and its relationship with Neo-Bioscore (Nb) scale (NbS) in neoadjuvant therapy (NeoT) has not been established. They could be predictive factors of response to double antiher2 blocking with Pertuzumab (Pz) and Trastuzumab (Tz). Methods: The efficacy of Chemo-trastuzumab (ChTz) versus Chemo-trastuzumab-pertuzumab (ChTzPz) was assessed in patients with eHBC treated at our center. We performed a comparative analysis of the pathological complete response (pCR) according to pre-treatment NLR and clinical NbS (Grade + clinical stage + estrogen receptor (ER) previous to NeoT) Univariate and multivariate retrospective study were performed using xi-square and binary logistic regression (v21 SPSS software). Results: 150 patients (Pts) with stage IIA to IIIC HBC were treated from 2014 to 2022. Mean age 52 years. 83 Pts (55.3%) received Chem-Tz and 67 Pts (44.7%) Chem-Tz-Pz. In the overall sample, the pCR was higher in the Tz-Pz group, 60% Vs 40%; OR 3.05 (95% CI 1.5-5.9). In the NLR >2 subgroup, pCR was higher in Pts treated with Pz-Tz, 66.7% vs 33.3%; OR 4.2 (95% CI 1.5 – 11.07) If we combine Pts with both NLR ≥2 and clinical Nb ≥2, the pCR was significantly higher in the Tz-Pz group, 68.4% vs 11.8%; OR 16.25 (95% CI 2.7-94.8). In the multivariate analysis, Nb≥2, NLR ≥2 and double blockade with Pz are related to an increase in pCR (OR 1.29, OR 1.076 and OR 2.90 respectively), with significance for Pz (p=0.001). Conclusions: In our review, the combined use of Pz-Tz proves to be a more effective treatment than simple Tz blockade in the treatment of poor prognosis breast cancer. High NLR, despite being a poor prognostic factor, seems to be a predictor factor of pCR in Pts treated with Pz-Tz. The increase in NLR and clinical NbS are factors to take into account to predict the efficacy of NeoT in eHBC Pts. [Table: see text]
Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with pembrolizumab in early-stage, triple-negative breast cancer.
Authors: White Olivia , Dent Susan Faye , Westbrook Kelly E. , Moore Heather
Published: June 2023

e12618

Background: KEYNOTE-522 demonstrated significant improvement in pathologic complete response (pCR) and event free survival (EFS) for early stage triple negative breast cancer (TNBC) patients (pts) treated with pembrolizumab (PEMBRO) and chemotherapy (carboplatin/paclitaxel weekly followed by doxorubicin/cyclophosamide (AC) every 3 weeks) in the neo/adjuvant setting. Standard of care prior to KEYNOTE-522 was AC every 2 weeks (dd), however, implementation of ddAC becomes impractical when accommodating 21-day PEMBRO dosing and creates concern for compromised efficacy. KEYNOTE-555 demonstrated feasibility of every 6-week PEMBRO dosing. We modified the KEYNOTE-522 regimen to employ ddAC with PEMBRO every 6-weeks with the aim to maximize clinical outcomes while reducing time spent in the infusion center. The primary objective is to compare the rate of pCR using ddAC plus 6-week PEMBRO versus PEMBRO and AC every 3 weeks. Secondary objectives include: safety of concomitant chemoimmunotherapy by comparing the incidence of adverse events (AEs) with PEMBRO (every 3 or 6 weeks), assessing rates of held cycles or dose modifications, and assessing toxicity of concomitant capecitabine and PEMBRO in the adjuvant setting. Methods: This was a retrospective, single-center, cohort study at Duke University Hospital (DUH). Results reported via descriptive statistics. Adult pts with clinical stages I-III TNBC were included in this study. Pts must have completed four cycles of AC. Pre-specified data collection points were obtained from the electronic health record and entered into a secure database. Results: A total of 25 female pts treated at DUH were included. The rate of pCR was 64.3% (AC) versus 81.8% (ddAC). All patients experienced at least one adverse event with their immunochemotherapeutic regimen. The most common IO-induced toxicities included thyroid-associated AEs (37.5%) and rash (37.5%). There were no grade 3 or 4 IO-induced toxicities reported. Five patients were on concomitant adjuvant capecitabine and PEMBRO for residual disease. One patient in each arm required dose adjustments for capecitabine and 3 patients had at least one deferred cycle. One patient experienced AEs associated with capecitabine. No patients had toxicities attributable to adjuvant PEMBRO. Conclusions: In this small single center study, the administration of neoadjuvant ddAC with PEMBRO at 400mg every 6 weeks was deemed feasible with no excess toxicity. There was a trend towards improved efficacy for patients treated with ddAC with PEMBRO. Additionally, safety endpoints were similar between groups. This dosing strategy allows for optimization of therapy with the incorporation of ddAC and adjuvant capecitabine, thus potentially improving outcomes in TNBC patients. Larger cohort studies, in the real-world setting, are needed to confirm these findings.
Decreased HER2 expression in residual disease following neoadjuvant therapy in patients with HER2-positive breast cancer.
Authors: Paredes Mogica Jan , Tang Haiming , Fischbach Neal A. , Zhan Haiying
Published: June 2023

e12621

Background: Human epidermal growth factor receptor-2 (HER2) overexpression is a defining feature of roughly 20% of localized breast cancer and represents a critical target for therapy. Since the demonstration that residual disease (RD) after neo adjuvant therapy (NAT) is associated with worse prognosis and that adjuvant ado trastuzumab emtansine (tDM1) improves survival, NAT has become the standard of care for localized HER2+ breast cancer. Retesting for HER2 overexpression post resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. The objective of this study was to evaluate the association of pre and post neo adjuvant therapy HER2 immunohistochemistry (IHC) expression on breast cancer outcomes in our institutional database. Methods: After IRB approval, data was gathered for patients with localized HER2+ breast cancer receiving NAT including trastuzumab/pertuzumab at Yale Cancer Center between 2012 and 2022. Pathologic complete response (pCR) was defined as no residual invasive tumor in breast and lymph nodes. Patients were divided into 3 cohorts by response and HER2 IHC: Cohort 1 pCR Cohort 2 pre-treatment 3+/post treatment 1-2+, and Cohort 3 pre-treatment 3+/post treatment 3+. A Kaplan-Meier survival analysis was done to assess recurrence free survival at 36 months. Results: Within the specified time interval, we identified 104 patients with localized HER2-IHC 3+ breast cancer who received neoadjuvant therapy. The pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had RD. Among patients with RD, 58.9% (23/39) remained HER2 IHC 3+ and 41% (16/39) had decreased HER2 expression IHC1+/IHC 2+. Median follow-up was 27.9 months at time of analysis. In patients with HER2 3+ RD 26% (6/23) developed local recurrence or distant metastasis while none of patients with HER2 IHC 1+ or 2+ RD had relapse ( p= 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis showed a significant difference between the 3 groups (log rank p= 0.004). Conclusions: In our retrospective cohort, decreased HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to select patients for more or less aggressive adjuvant therapy, stratify patients in adjuvant trials, and identify patients who may benefit from more intensive post therapy surveillance.
De-escalating therapy dilemma in small HER2 positive node negative breast cancer.
Authors: Hajjaji Nawale
Published: June 2023

e12626

Background: Neoadjuvant therapy (NAT) is the standard of care for locally advanced HER2 positive breast cancer (BC) and provides pathologic complete response (pCR), a key prognostic factor and indicator to decide whether to escalate to adjuvant T-DM1 in case of residual disease, as per the KRISTINE trial. However, optimal sequencing of treatment (NAT vs. surgery first) is less clear in T1cN0 (stage I) HER2 positive BC. Moreover, the long-term follow-up of the Adjuvant Paclitaxel and Trastuzumab (APT) trial showed that deescalating chemotherapy is a possible strategy for small HER2-positive node negative breast cancers when tumor size is 3 cm or less. In clinical practice, there is a recurrent debate in multidisciplinary boards to decide the adequate strategy in small HER2 positive node negative BC. Although these tumors are considered of good prognosis, recent results by An et al. 2022 fuels the debate. They showed in a large observational cohort that T1N0 HER2 positive BC APT eligible treated with NAT and not achieving pCR have similar survival to patients with T2N0 tumors with residual disease, suggesting a higher risk group among small tumors.The aim of the study was to analyze the profile and outcome of APT eligible patients treated with NAT using a detailed tumor size breakdown. Methods: APT eligible patients treated with NAT were identified among a real-world cohort of 340 early HER2 positive BC patients receiving NAT at Oscar Lambret Cancer Center (Lille, France). The outcome of the APT eligible patients (n = 115) was analyzed according to tumor size ( < 15mm, 15-20mm, 21-30mm). Results: All patients were female with a median age of 54 years and received neoadjuvant anthracyclines followed by taxanes and trastuzumab. The ratio of hormone receptor (HR) positive / HR negative tumors was 72% / 28%. A similar distribution of grade 2 / grade 3 tumors was observed. Up to 75% of the patients did not have a complete pathologic response to NAT. In HR positive, the pCR rate was 43% in HER2 positive tumor of less than 15mm, 26% in tumors of 15-20mm, 25% in tumors of 21-30mm, and 32% in tumors of 31-50mm. In HR negative tumors, pCR rate was 81% in tumors of 15-20mm, 56% in tumors of 21-30mm, and 67% in tumors of 31-50mm. Conclusions: These results showed that APT eligible small HER2 positive and HR positive tumors had low chemosensitivity leading to adjuvant treatment escalation as per standard of care. It raises questions about the appropriate selection of patients for de-escalation in this population subset.
Association of KMT2C loss-of-function mutations in circulating tumor DNA and prolonged response to the combination of PARPi and PI3Ki.
Authors: Batalini Felipe , Ke Shizong , Liu Ruolin , Blewett Tim , Rhoades Justin , Gulhan Doga , Konstantinopoulos Panagiotis A. , Matulonis Ursula A. , Adalsteinsson Viktor , Wulf Gerburg M.
Published: June 2023

e13003

Background: The emergence of somatic KMT2C mutations has been associated with resistance to various treatments, including chemotherapy and endocrine therapy in patients with estrogen receptor-positive breast cancers. The impact of these mutations in patients treated with poly-ADP ribose polymerase inhibitors (PARPi) and phosphatidylinositol-3-kinase inhibitors (PI3Ki) is unknown. Methods: Circulating tumor DNA (ctDNA) was obtained from plasma and peripheral blood at different time points from 38 patients prior to treatment with the combination of the PARPi olaparib with the alpha-specific PI3Ki alpelisib (NCT01623349). CtDNA was also collected immediately before the first cycle and at the time of disease progression. CtDNA underwent deep targeted sequencing (tumor-normal pairs, 397 genes (2Mb) at 25,000x somatic and 10,000x germline) at the Broad Institute of MIT and Harvard. Variants that were exonic, non-synonymous, and predicted to lead to loss-of-function were considered mutations. Cohorts were stratified according to the presence or absence of the genomic alteration, and progression-free survival was compared with the Kaplan-Meier method and log-rank test. A Cox regression was performed using age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines of treatment as covariates. Results: The KMT2C gene was one of the 3 genes most frequently mutated in our cohort, affecting 5 patients (15%) after the exclusion of those with variants with non-deleterious alterations. The other 2 commonly mutated genes were TP53 (76%) and PIK3CA (15%). In the comparison of patients based on these most common mutations, we identified that patients with somatic KMT2C mutations (n=5) have longer mPFS than those that were wild type (n=28): mPFS 386 vs. 151 days, log-rank p = 0.025. Cox proportional hazards model accounting for age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines revealed a hazard ratio of 0.16; p = 0.007. All somatic KMT2C mutations were proximal to the SET domain critical for methyltransferase activity. Upon progression, the KMT2C-mutated clones were suppressed to below the detection level of mutation calling algorithms. Analysis of the raw files revealed that the clones were suppressed but not eliminated. Conclusions: While the emergence of KMT2C has been reported to be associated with cancer progression and resistance to different therapies, patients with deleterious KMT2C mutations in the ctDNA may benefit from therapy with PARPi and PI3Ki.
PI3KCA mutation prevalence and outcome among patients with metastatic breast cancer in Bulgaria treated with first-line endocrine therapy.
Authors: Gencheva Radostina , Hadjidekova Savina , Petrova Mila , Krustev Dimo , Kraleva Petya , Zhbantov Georgi , Conev Nikolay Vladimirov , Stoyanov Dragomir Svetozarov , Arabadjiev Jeliazko Iliev , Tazimova Eliz , Bachurska Svitlana , Galev Ivan , Eneva Mariyana , Tsvetkova Mariela , Staneva Rada , Dimitrova Eleonora , Hadjiev Rossen , Donev Ivan
Published: June 2023

e13005

Background: There are phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations in 30-40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2) tumor samples. Nevertheless, clinical outcomes in this group vary amongst research trials. Methods: We sought to determine the incidence of PIK3CA mutations in Bulgarian patients with metastatic HR+, HER2-negative breast cancer, as well as to evaluate and compare progression-free survival (PFS) in the real world between wild-type (WT) and mutant cohorts. In this multicentric retrospective analysis, 250 tissue samples were collected between 2016 and 2022 from three Bulgarian oncology centers. Qualitative real-time PCR was used to determine the existence of PIK3CA mutations. The median follow-up time was 28 months. Results: The mean age was 57.6±11.6 years for the mutant cohort and 56.5±12.2 for the wild-type cohort (p=0.52). The percentage of patients with visceral metastatic disease was 58.8% (n=147). Postmenopausal patients were 84.3% (n=210). PIK3CA mutation prevalence was 29.2% (n=73). The most prevalent mutation was found in exon 20: H1047R (9.2%). Among all clinicopathological features, we observed only a significant relation between the presence of a mutation and a metastatic stage at diagnosis (p = 0.002). 67.1% of the patients received endocrine therapy (ET) + CDK4/6 inhibitor as first-line therapy, while the remainder receive ET monotherapy. Patients with PIK3CA mutation did not have significantly different median PFS compared to WT patients (32 months (95%, CI: 22-40) versus 24 months ((95%, CI: 21-36) (p=0.45)); HR=0.86 (95%, CI: 0.5-1.3) (p=0.46). In propensity matching score analysis (matched for treatment utilized as a first line ET, menopausal status, and locations of metastatic disease), we confirmed our finding (36 months (95%, CI: 20-40) versus 26 months (95%, CI: 21-38), p = 0.69). Conclusions: We demonstrated that the prevalence of PIK3CA mutations in Bulgarian patients is comparable to that reported in other countries. Our findings suggest that the presence of a PIK3CA mutation has no effect on the efficacy of endocrine therapy of first-line treatment. In summary, our study provides valuable insights into the topic, but limitations including the retrospective design and small sample size suggest that the findings need to be replicated by more robust studies and larger sample sizes to draw definitive conclusions.
Real-world safety and effectiveness of CT-P6 (biosimilar trastuzumab): A post-marketing surveillance study in Korea.
Authors: Park Min-Ho , Kim Tea Hyun , Seo Jae Hong , Park Jung Ho , Seong Min-Ki , Park Keon Uk , Kim Min Kyoon , Chang Myungchul , Koh Su-Jin , Lee Moon Hee , Lim Seung Taek , Yoo Young Bum , Oh So Yeon , Kim Sung Hyun , Park Tae Hong , Ju Hana , Baek Eric Hyungseok , Kim Sinhye , Kim Nahyun , Lee Eunkyung
Published: June 2023

e13025

Background: CT-P6 is a biosimilar trastuzumab product approved in many countries worldwide, including the European Union and the United States. This study aims to confirm the safety and effectiveness of CT-P6 in routine clinical practice settings for the approved indications of HER2-positive metastatic breast cancer (MBC), early breast cancer (EBC), and metastatic gastric cancer (MGC) in the Republic of Korea. Methods: The observational, prospective, multi-center, post-marketing surveillance (PMS) study was conducted from October 5, 2018 to October 4, 2022, on Korean patients diagnosed with MBC, EBC or MGC and newly treated with CT-P6 regardless of previous treatment of trastuzumab products other than CT-P6. Patients receiving at least one CT-P6 treatment according to the prescribing information and being monitored for safety and effectiveness were included in these analyses. Safety was evaluated by all types of adverse events (AEs), including adverse drug reaction (ADR), and serious adverse event (SAE); for up to a year after the first dose of CT-P6. Safety was further summarized by background factors (demographic and clinical characteristics) for subgroup analysis to identify variables independently affecting the incidence proportion. As for effectiveness, disease-specific clinical response (by best overall response for MBC and MGC; disease progression, and pathologic complete response (pCR) for EBC) were assessed for up to one year. Results: The safety population included 642 patients (94 MBC, 494 EBC, 54 MGC). For patients with MBC, AEs occurred in 71.28%, ADRs in 48.94%, and SAEs in 19.15%. For EBC, AEs occurred in 43.52%, ADRs in 26.52%, and SAEs in 6.48%. In case of MGC, AEs occurred at a rate of 79.63%, ADRs at 40.74%, and SAEs at 14.81%. Overall, the incidence of ADR was statistically different for groups ≥65 of age ( p=0.0323); comorbidity or complication, especially with cardiac disorder ( p=0.0018); and previous chemotherapy ( p=0.0002). In terms of effectiveness, positive outcomes were observed. Conclusions: CT-P6 administered to Korean patients according to the prescribing information was well tolerated, with no new safety signals identified. The safety and efficacy profiles of CT-P6 in a real-world population were consistent with those observed in the previous clinical studies. [Table: see text]
Palbociclib, trastuzumab, pyrotinib and fulvestrant in patients with brain metastasis from ER/PR positive, HER-2 positive breast cancer: Report from an interim analysis of a multicenter, prospective study in China.
Authors: Hong Ruoxi , Xu Fei , Lu Yongkui , Du Caiwen , Yuan Zhongyu , Shi Yanxia , Xia Wen , Wang Shusen
Published: June 2023

e13032

Background: HER2-positive breast cancer patients are at a high risk of developing metastases in brain. Effective treatment should involve anti-HER2 targeted therapy. This aim of this study is to evaluate the activity of the chemo-free combination of palbociclib, trastuzumab and pyrotinib with fulvestrant in ER positive, HER2-positive breast cancer patients with brain metastasis. Methods: We did a multi-center, prospective trial in three hospitals in China. Female patients older than 18 years who had whole brain radiotherapy-naive ER/PR positive, HER2-positive brain metastases with an Eastern Cooperative Oncology Group performance status of 0–2 were treated with palbociclib, fulvestrant, combined with trastuzumab and pyrotinib, and until disease progression or intolerable adverse effects. The primary endpoint was objective response rate in the central nervous system (CNS), as assessed by investigator per the modified Response Evaluation Criteria In Solid Tumours (version 1.1). The study is still ongoing and recruiting. Here we report the results of an interim analysis. The study is registered with ClinicalTrials.gov, NCT04334330. Results: Between December 4, 2020 and November 2, 2022, 15 patients were enrolled. Eleven patients had prior exposure to trastuzumab. In the 14 patients who were evaluable for clinical response, the objective response rate in the CNS was 28.6%? (95% CI, 8.4% - 58.1%). At a median follow-up of 6.3 months (range, 2.1-14.3 months), the median PFS was 10.6 months (95%CI, 4.3 – 16.9 months). The time to progression in the CNS was 8.5 months (95%CI, 5.9 – 11.1 months). Conclusions: Combination of palbociclib, trastuzumab and pyrotinib with fulvestrant represents an active chemo-free treatment strategy in hormonal receptor positive, HER2-positive breast cancer patients with brain metastasis. Clinical trial information: NCT04334330 .