bluuebunny/crossref_metadata_2025 huggingface dataset:
Time to surgery after neoadjuvant chemotherapy in breast cancer and its impact on survival in a middle-income country.
Authors: Garcia Katherine , Sandoya Lorena , Morquecho Walter , Paulson Guillermo , Santacruz Mayra , Castro Norma , Engracia Ruth
Published: June 2024

e12640

Background: The time to surgery after neoadjuvant chemotherapy (NACT) in breast cancer and its impact on survival has not been sufficiently evaluated in low- or middle-income countries. The objective of this study was to analyze the impact on overall survival in a cancer hospital in Guayaquil, Ecuador. Methods: This is a retrospective study carried out at the SOLCA Guayaquil Hospital in Ecuador from January 2009 to December 2011. The inclusion criteria were women ≥18 years old, diagnosed with invasive breast cancer in stages II and III, who were treated with NACT followed by surgery. The data were collected from clinical records; those with incomplete data were excluded, and the variables age, stage, lymphovascular invasion (LVI), and pathological response were included. Survival was grouped into <8 and ≥8 weeks for the comparative analysis. Survival time was calculated from diagnosis by biopsy until death; A p-value of ˂0.05 was taken as significant; The Kaplan-Meier estimate was used for overall survival, then the groups were compared by Log Rank, and the influence of the covariates was estimated in the Cox regression model. The data were analyzed in an SPSS v29 statistical program. Results: 200 patients were identified, 195 of whom had all the information for the analysis. The median time between the end of NACT and surgery was 7.57 weeks (range, 2.43-29.14 weeks). In the < 8 and ≥ 8 weeks group, there were 111 and 84 patients, respectively. The clinical characteristics are described in the Table. The median overall survival in the entire cohort was 8.32 years (CI: 6.68-9.96), and for the < 8 and ≥ 8 weeks groups, it was 10.0 and 6.56 years, respectively, with a Log-Rank of 0.031. The follow-up (median) of the entire cohort was 7.54 years (range 0.63 – 10.99 years). The multivariate Cox regression showed that LVI, HR: 2.35 p<0.001; clinical stage III (II vs III), HR: 2.47 p<0.001; residual disease (pathological complete response vs residual disease), HR: 2.70 p=0.012; age ≤ 50 years (≤ 50 years vs > 50 years), HR: 1.69 p=0.011; were factors that statistically contributed to worse survival, however, the time between the end of NACT and surgery < 8 and ≥ 8 weeks (p = 0.07) had no statistical impact on survival. Nonetheless, a numerical trend towards better survival was noted in the < 8 week group. Conclusions: The delay in time to surgery after NACT had a negative trend in survival, although it was not statistically significant, which may be due to the small sample size. [Table: see text]
Circulating tumor DNA (ctDNA) to predict response to neoadjuvant chemotherapy (NAC) and prognosis in patients (pts) with early breast cancer (BC).
Authors: McHayleh Wassim , Young Ashley , Burkovskaya Valeria , Galuia Mariem
Published: June 2024

e12642

Background: pCR to NAC is an important predictor of clinical recurrence. Up to 16% of patients with pCR may experience disease recurrence, 45% of patients with RD do not. Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response EBC patients receiving NAC. We evaluated whether ctDNA status and dynamics can predict the tumor response to NAC and the risk of recurrence in patients with EBC. Methods: We conducted an observational, retrospective, single-center study to investigate whether ctDNA can predict tumor response to NAC and prognosis in BC patients. 74 pts received standard of care NAC;g 4 patients were treated in the adjuvant setting. Blood samples were collected at diagnosis from 44 pts (baseline) and longitudinally during treatment from 34 patients. Tumor response and progression outcomes were reported. A clinically validated, tumor-informed ctDNA assay (Signatera). ctDNA status and dynamics were correlated with pathologic and radiologic outcomes. Results: 29 TNBC pts were ctDNA+ at baseline, 6 were ctDNA- Of the 29 pts, early ctDNA clearance by week 6 of NAC was observed in 10 pts, weeks 7-16 in 9 pts, clearance post-surgery in 1, 3 pts remained ctDNA+ after surgery, serial ctDNA testing is underway for the remaining 6 pts. All TNBC patients who had radiological complete response (CR) had early clearance of ctDNA . All pts with persistent ctDNA positivity levels after completion of NAC had radiological partial response (PR). Of the 9 TNBC pts with undetectable baseline ctDNA, 33% achieved CR on MRI and 43% achieved pathologic CR. Of the 19 TNBC pts with ctDNA clearance in response to NAC, 89% (17/19) remained ctDNA- and with no evidence of disease (NED) (length of follow up). 1 pt initially cleared their ctDNA on NAC, turned ctDNA+ 4 weeks prior to radiological recurrence. 1 pt with ctDNA clearance on NAC remained ctDNA post-surgery but experienced recurrence. All (n=3) TNBC pts with persistent ctDNA-positivity levels after curative treatment (NAC and surgery) had disease recurrence. The remaining 6 pts ctDNA are ongoing NAC. Of the 6 pts with undetectable baseline ctDNA, 6/6 continued to be ctDNA- regardless of their disease status. At diagnosis, 8/9 ER+ ps were ctDNA+. 3/8 (38%) ER+ pts with positive baseline ctDNA had early clearance of ctDNA after NAC. All 3 had residual disease on pathology. 2/8 (25%) remained ctDNA+ after surgery and neither achieved radiologic CR or pCR. The remaining 3 pts are ongoing NAC. Conclusions: In early TNBC, ctDNA monitoring can be used to predict tumor response to NAC and tailor therapeutic regimens. ctDNA persistence can predict early recurrence and helps identify patients in which treatment escalation or enrollment on clinical trials is necessary. In ER positive breast cancer, and despite the small number of patients, ctDNA clearance does not predict response to NAC.
Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.
Authors: Jiang Bei , Pugacheva Elena , Santiago Stell Patadji , Wen Sijin , Hill Jordan , Hartzell Michelle , Khan Hiba , Sakkal Laila , Hafez Maria
Published: June 2024

e12645

Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.
Outcome with pertuzumab, docetaxel, and trastuzumab (PTH) regimen in patients with HER2 positive metastatic breast cancer: Real-world data from a single center in India.
Authors: Gogia Ajay , Gupta Anshul , Batra Atul , Deo S.V.S , Sharma Daya Nand , Mathur Sandeep , Mishra Ashutosh , Prasad Chandra Prakash
Published: June 2024

e13037

Background: Pertuzumab, Docetaxel and Trastuzumab (PTH) regimen constitutes one of the standard treatment regimens in human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The real-world outcomes of its use from the Indian sub-continent are lacking. Methods: We retrospectively reviewed the medical records of HER2-positive MBC treated with an upfront PTH regimen at the All India Institute of Medical Sciences, New Delhi, India, between Aug 2016 to July 2023. A total of six cycles of PTH [pertuzumab (840 mg loading followed by 420 mg), docetaxel (75 mg/m2), trastuzumab (8 mg/kg loading followed by 6 mg/kg) q21 days] were planned along with granulocyte-colony stimulating factor (GCSF) prophylaxis. Patients were continued on maintenance trastuzumab after 6 cycles (till disease progression) and hormonal agent if indicated. The primary outcome was progression-free survival (PFS). The secondary outcome was overall survival (OS), overall response rate (ORR) rates, and toxicity. Results: Eighty-seven were included with a median age of 48 years (range, 25-73). Overall, 38 (43.6%) patients had hormone-positive (estrogen receptor and or progesterone receptor) disease and 48 (55.17%) were premenopausal. Thirty-five (40.2%) patients had received prior adjuvant and neoadjuvant treatment. Eighty patients (91.5%) had visceral metastasis and the most common site was the liver followed by the lung. After a median follow-up of 36 months, the median PFS was 15 months and OS was 42 months. The ORR was 85.3% and complete response (CR) was observed in 14(16.09%) patients. The survival outcomes were significantly better among those with hormone-negative disease and among those who achieved CR after 6 cycles of PTH. Grade 3/4 toxicity was seen in 12% of patients which led to dose modification, interruption, and change in chemotherapy. Two patients developed reversible left asymptomatic ventricular systolic dysfunction. None of the patients developed congestive heart failure. The most common grade 3/4 toxicities were diarrhea in 8 (9.1%) patients, cutaneous rash in 2 (2.2%) patients and thrombocytopenia in 2 (2.2%) patients. There were two cases of febrile neutropenia. Conclusions: In a real-world context, PTH is an effective and well-tolerated regimen for in patients with HER2-positive MBC in India. Hormone-positive disease has poor survival compared with hormone negative disease.
Employing semi-quantitative methods to classify breast cancer markers (ER, PR, HER2, Ki67) expression, using the RT-qPCR based APIS Breast Cancer Subtyping Kit.
Authors: Gasior Anna , Wegscheider Anne-Sophie , Paveley Jack , Howard Kimberly Jane , Harrison Mathew , Gough Leanne , Gorniak Joanna , Rollinson Sara , Pounce Zoe , Niendorf Axel
Published: June 2024

e13091

Background: Accurate determination of breast cancer (BC) biomarker status is crucial for guiding patient management decisions. Histopathologists commonly use semi-quantitative scoring systems to convert subjective observations of immunohistochemistry (IHC) marker expression into quantitative data, allowing a more detailed categorisation of marker status. The APIS Breast Cancer Subtyping Kit (BCSK) is an in vitro diagnostic test, detecting the relative expression of seven mRNA target genes ( ESR1, PGR, ERBB2, MKI67, CCNA2, PCNA, and KIF23) from invasive BC tissue. The APIS BCSK reports a positive/negative result for each biomarker alongside a molecular classification. Here, we demonstrate that by implementing additional RNA expression cut-off values, it is possible to generate a semi-quantitative result by further stratifying target expression into negative, low, medium, and high status using the APIS BCSK. Methods: 368 formalin-fixed paraffin-embedded (FFPE) samples of BC cases were used, obtained by core needle biopsy or resection. IHC scores were correlated with copy numbers as determined by an independently validated digital PCR (dPCR) assay and were used to set copy number cut-off values corresponding to IHC classification. The generated dPCR cut-off values were used to evaluate the corresponding ∆Ct values (RNA expression results derived from the APIS BCSK). For each target, three ΔCt cut-offs were established, facilitating classification into negative, low, medium, and high expression. Results: The semi-quantitative approach successfully classified target expression levels ( ESR1, PGR, ERBB2, MKI67). Overlap in ΔCt values was observed in central IHC categories for all targets, likely due to tumor heterogeneity and differing measurement methods for IHC and RT-qPCR. Despite these discrepancies, the derived cut-off values define a semi-quantitative scale for each target (Table). Conclusions: This study has established a methodology that utilises target copy number values and IHC protein quantification to establish ΔCt cut-off points. For each target we have defined four distinct groups as negative, low, medium, and high expression. This approach provides a semi-quantitative scale for evaluating each target with the APIS BCSK and serves as a valuable tool for classifying and understanding target expression levels. [Table: see text]
Efficacy and safety of abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer: A systematic review and meta-analysis.
Authors: Altaf Faryal , Qureshi Zaheer , Jamil Abdur , Siddique Rimsha , Fatima Eeshal
Published: June 2024

e13096

Background: Breast cancer, particularly the HR+/HER2- subtype, remains a major global health concern. Abemaciclib, a CDK4/6 inhibitor, has shown promise in treating advanced cases. This study comprehensively assesses the efficacy and safety of Abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer. Methods: Following PRISMA guidelines, a systematic review and meta-analysis were conducted. A thorough literature search spanning PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov identified 22 studies. Inclusion criteria encompassed RCTs and retrospective cohort studies reporting on Abemaciclib in approved doses, either as monotherapy or in combination. Outcome assessments included PFS, ORR, SE/AE, and OS. Quality assessment utilized ROB II and NOS tools. Results: Analysis of 22 studies involving 14,010 patients revealed that Abemaciclib significantly improved PFS and ORR, with a 47% and 46% reduction in risk, respectively. A noteworthy 24% reduction in the risk of death was observed in the Fulvestrant combination group. However, Abemaciclib increased the risk of SE/AE by 104% and 304% in the Fulvestrant and NSAI combinations, respectively. Conclusions: Abemaciclib, particularly in combination with Fulvestrant, emerges as an effective therapeutic option for HR+/HER2- advanced or metastatic breast cancer, improving PFS and OS. The higher toxicity profile warrants cautious use, especially in treatment-naïve patients. This review informs future research directions and offers insights for clinical decision-making in the evolving landscape of breast cancer treatment.
Feasibility and tolerability of eribulin-based chemotherapy versus other chemotherapy regimens for patients with metastatic triple-negative breast cancer: A single-centre retrospective study.
Authors: Wang Lili , Huang Weiwei , Wang Chenxi , Chen Qi , Shen Yangkun , Huang Zhijian , Liu Jian , Lin Xiaoyan , Wu Fan , Chen Xinhua , Li Nani , Hong Yi , Chen Mulan , Li Jieyu , Huang Chuanzhong , Yu Suhong
Published: June 2024

e13135

Background: Patients with Triple-negative breast cancer (TNBC) face a poor prognosis and limited therapeutic options. Current data on eribulin usage to treat TNBC is scarce. Therefore, we sought to compare the feasibility and tolerability of eribulin-based regimens with other chemotherapy regimens in patients with TNBC. Methods: This retrospective study was conducted at Fujian Medical University Cancer Hospital and included 159 patients with TNBC enrolled between October 2011 and January 2023. Patients underwent treatment with eribulin-based and other chemotherapy regimens. The study's primary endpoints were progression-free survival (PFS) and overall survival (OS), while its secondary endpoint was objective response rate (ORR), disease control rate (DCR), and safety. Tumour response was assessed using RECIST V.1.1 criteria. Results: Of the 159 participants in the study, 42 individuals (26.4%) received treatment with eribulin, whereas 117 participants (73.6%) were administered alternative chemotherapy regimens, which included nab-paclitaxel-based therapy (n=45) and platinum-based therapy (n=51). The follow-up period for all patients ended on December 31st, 2022, and the median follow-up time was 18.3 months (range:0.7-27.5). Following propensity score matching (PSM), eribulin-based treatment resulted in longer median PFS compared to platinum-based (hazard ratio (HR)=0.41, p=0.006), nab-paclitaxel-based (HR=0.36, p=0.001) and other chemotherapy (HR=0.39, p<0.001). Also, eribulin induced a remarkable prolongation of the median OS duration in all three comparative groups. The group receiving eribulin treatment showed significantly reduced incidences of any grade of anaemia, peripheral neuropathy, nausea and vomiting, and hair loss compared to other chemotherapy groups. Conclusions: For the salvage treatment of advanced TNBC, treatment with eribulin produced longer median PFS and OS than other chemotherapy regimens, with a well-tolerated safety profile. Therefore, further investigation of eribulin-based treatment in larger randomized trials for patients with advanced TNBC is warranted. Clinical trial information: NCT05953909 .
Treatment patterns of adenoid cystic carcinoma of the breast: A systematic review.
Authors: Macias Jonathan , Sales Nogueira Amorim Canedo Felipe , Lu Shou-En , Chen Chunxia , Heleno Caio Teixeira , Bridgeman Matthew , Goncalves Priscila Hermont , George Mridula Annette
Published: June 2024

e13147

Background: Adenoid cystic carcinoma of breast (ACC-B) is a rare subtype of breast cancer (BC) accounting for 0.1% of all BCs. It shares histologic features with ACCs arising in the salivary glands and other locations. Given the hormone receptor (HR) negative phenotype [negative expression of the estrogen receptor (ER), progesterone receptor (PR)], some clinicians treat ACC-B as a basal subtype of BC, which is predominantly treated with chemotherapy. However, ACC-B has a more indolent and favorable clinical behavior. There are no established treatment guidelines for ACC-B. We conducted a systematic review of the literature on the treatment patterns for ACC-B. Methods: We followed the PRISMA criteria using the database in Cochrane, Embase, PubMed, Scopus, and Web of Science. The Covidence software was used for screening and data extraction. Eligible studies discussed the management of stage I-III ACC-B from 1960 to 2022. Individual patient (pt) demographics, tumor characteristics, treatment and outcomes were collected, when available. Results: The database search found 2864 studies, of which 187 articles met the inclusion criteria in the study protocol. Given the rarity of this subtype of BC, most studies were case reports (n=104). A total of 4370 pts with a median age of 57 years were eligible for analysis. Information on ER, PR and HER2 status was not available for all cases. For the cases in which this was reported, most were ER and/or PR negative (76% ER negative and 83% PR negative). Surgery was the primary treatment reported for 3984 pts. A total of 21.5% underwent mastectomy, 40.7% lumpectomy and 37.7% were treated with other modalities of surgery. In the group of patients for which information was available regarding the receipt of systemic therapy (n=3147), 82% did not receive neoadjuvant or adjuvant chemotherapy. Metastatic disease was reported to have developed in 2.2% of the total patients (n=98). Median time to recurrence was 31 months (0-460) with a median overall survival of 134 months (1-462). The most common site of metastases were the lungs (60%). Among the patients who developed metastatic disease and for whom initial treatment information was available; radiation was given to 32 pts, 26 received adjuvant chemotherapy and 15 received both radiation and chemotherapy. No patients that developed metastatic disease received neoadjuvant chemotherapy. Conclusions: Our results suggests that ACC-B has a clinical behavior different from basal subtype of BC. In our review, only 2.2% of pts relapsed with metastatic disease, even though most of the pts did not receive prior systemic therapy. We need to better understand the genomic landscape of ACC-B, to identify pts who may be at risk for recurrence and develop specific guidelines to treat this rare type of BC.
The long noncoding RNA MANCR to promote and stabilize triple negative breast cancer.
Authors: Warren Janine , Banerjee Bodhisattwa , Stein Janet , Stein Gary , Lian Jane
Published: June 2024

e13150

Background: Cancer remains a leading cause of death worldwide, despite many advances in cancer treatment over the past decade. Triple Negative Breast Cancer (TNBC) is among the highest with a poor prognosis. Early diagnosis and modern treatment regimens for breast cancer (BC) have led to a high disease-free survival rate. Still, survival decreases significantly for patients with metastatic disease. Long non-coding RNAs are among a recent class of epigenetic regulators that function in the nucleus to support the stability of the cells and maintain the fidelity of chromatin interactions. Our laboratory discovered the long noncoding RNA MANCR (LINC00704) as being upregulated in human BC tumors and this is indicative of a worse survival rate than in patients with low MANCR-expressing tumors. MANCR is aberrantly expressed in TNBC cells, and these cells are highly dependent on MANCR to retain their tumorigenic characteristics. Methods: Our functional in vitro studies in MDA-MB-231 TNBC cells used GapmerRs to knockdown MANCR. For in vivo studies, TNBC cells were injected into the 4th mammary fat pad of mice, allowed initial tumor formation, and then treated the animals with 2 nmol/g of a negative control or MANCR targeting GapmeR. We also identified genome interaction sites at single nucleotide resolution by chromatin isolation by RNA purification (ChIRP)-seq to determine the mechanism of MANCR activity in TNBC cells. Results: We found that MANCR knockdown promotes DNA damage and decreases cell proliferation, migration, anchorage-independent colony formation, transwell invasion, and overall survival. Additionally, targeting MANCR in animals with existing tumors drastically inhibited tumor growth and the end-point tumor mass over time. The MANCR GapmeR treatment also inhibited the ability of TNBC cells to circulate and disseminate to distant organs. After performing ChIRP-seq in the MDA-MB-231 cells, we identified 988 genome-wide binding sites that exhibit MANCR interactions, of which 79% are intergenic and 21% are genic regions. Furthermore, 127 MANCR ChIRP peaks were found to overlap with fragile sites in the genome, indicating MANCR provides stability to these sites. Conclusions: These data suggest that targeting MANCR has therapeutic potential for patients with “MANCR-high” TNBC tumors by disrupting genome stability. Indeed, our in vivo studies demonstrate that “MANCR-high” TNBC tumors require MANCR to rapidly grow and promote disease progression. Lastly, many of the MANCR-chromatin interactions identified were found in intergenic regions and overlap with fragile sites within the genome. Collectively these data strongly indicate that MANCR stabilizes the TNBC genome, and disrupting genome stability by targeting MANCR has therapeutic potential.
Novel prognostic staging system for patients with de novo metastatic breast cancer: A real-world experience.
Authors: Khamees Ibrahim , Mahadevia Himil , Gosch Kensey , Sharma Parth , Chandra Simran , Gast Kelly C. , Pluard Timothy J. , Hensing Whitney L.
Published: June 2024

e13167

Background: De novo metastatic breast cancer (dnMBC) is a heterogenous disease with variable survival rates. For newly diagnosed, non-MBC, the AJCC staging system incorporates non-anatomical factors, biomarkers and grade, in addition to tumor size and nodal status to define the prognostic stage group. These variables and other disease-related factors, such as sites of metastasis, have been associated with survival in MBC. Despite this, the current staging system groups all patients with dnMBC into a single prognostic group. More tools are needed to help clinicians relay important prognostic information to patients with dnMBC. Plichta et al. [1] utilized large population data sets to develop a novel staging system for dnMBC, which successfully stratified patients into four prognostic groups (IVA-D) based on disease-related variables. In this study, we sought to validate this staging system in an independent, real-world cohort of patients with dnMBC. Methods: We used a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based healthcare system in the Kansas City metro area. The KABCC is a multidisciplinary clinic dedicated solely to the care of patients with MBC. Patients with dnMBC were assigned prognostic stage IVA, IVB, IVC, and IVD according to the system developed by Plichta et al. [1]. Overall survival (OS) was compared between groups using Kaplan-Meier analysis and the log-rank test. We also performed a stratified analysis based on age at diagnosis, <60 years versus ≥60 years. Results: Ninety-seven patients with dnMBC were included in the analytic cohort. Mean age at diagnosis was 60 years, and most patients self-identified as non-Hispanic White (71.1%) or Black (22.7%). Nine patients were assigned stage IVA (9.3%), 39 stage IVB (40.2%), 32 stage IVC (33%) and 16 stage IVD (16.5%). Most stage IVA were HER2 positive (66.7%), while most stage IVD were triple-negative (56.3%). OS differed significantly between the four stage groups, with mortality rates increasing as stage increased. This was true in both the overall population (p<0.001) and when patients were stratified by age at diagnosis (both p<0.05) (Table). Conclusions: In an independent, real-world cohort of patients with dnMBC, a novel prognostic staging system that incorporates biomarkers, T-stage, grade, and sites of metastasis successfully stratified patients into four prognostic groups. Our findings help to confirm the utility of this staging system in dnMBC. [Table: see text]
Preclinical analysis of the efficacy of near-infrared photoimmunotherapy and anti-PD-1 antibody combination therapy for treating CD73-positive lung cancer.
Authors: Chiba Ryohei , Nakajima Kohei , Hatanaka Kanako C , Ujiie Hideki , Aragaki Masato , Kobayashi Takuma , Konishi Teppei , Kinoshita Ichiro , Hatanaka Yutaka , Ogawa Mikako , Kato Tatsuya
Published: June 2024

e14521

Background: The CD73/adenosine pathway, which converts extracellular ATP to adenosine, is emerging as a promising target for immunotherapy in various cancers. In the tumor microenvironment, hypoxia triggers upregulation of adenosine-activating molecules, including CD73, a membrane-anchored enzyme expressed on cancer cells. CD73 induces the expression of PD-1 and CTLA4, and all of this leads to immunosuppression. Therefore, we focused utilizing near-infrared photoimmunotherapy (NIR-PIT) to kill CD73-expressing cells and alleviate immunosuppression. NIR-PIT is an innovative cancer treatment approach which involves irradiating NIR light after the administrated antibody-photosensitizer conjugate binds to the target cells. Methods: In vitro, anti-CD73 antibody-IR700 conjugate was prepared and added to the CMT167 and LLC cell lines, which were irradiated with NIR light under a microscope. In vivo, a mouse model was established using the CMT167 cell line. The mice were divided into 6 groups: 1) NIR-PIT group against CD73; 2) anti-PD-1 antibody group; 3) combined treatment group of 1) and 2); 4) control group; 5) anti-CD73 antibody-IR700 conjugate group; and 6) near-infrared light irradiation group. Tumor volume and survival rate were compared among these groups. Additionally, after 2 weeks of treatment, tumors in the four groups 1) to 4) above were pathologically evaluated using two different AI-equipped software programs. Results: Microscope observation revealed that NIR-PIT induced immunogenic cell death of CD73-positive mouse lung cancer cell lines in vitro. In vivo, the effect of NIR-PIT on this mouse model was also demonstrated. Although previous studies have shown the efficacy of treatment with anti-CD73 antibodies, the present study compared the CD73-IR700 conjugate group to the NIR-PIT to CD73 group, and the latter group showed better therapeutic outcomes. Additionally, the combined treatment group displayed the highest anti-tumor efficacy in terms of survival and tumor volume. Pathological evaluation of the tumor interior showed a significant increase in tumor-infiltrating lymphocytes compared to the other groups. Additionally, the percentage of tumor cells was significantly reduced, while the percentage of stroma, including fibrous tissue, was significantly increased. In line with other studies that have already reported the additive effect of combination therapy with anti-CD73 antibodies and immune checkpoint inhibitors, the present study showed that the combination therapy resulted in further activation of immune cells and enhanced the therapeutic effect. Conclusions: CD73 represents a promising target for NIR-PIT, with potential for enhanced effectiveness when used in combination with immune checkpoint inhibitors.
Correlation of distinct circulating cytokine/chemokine profiles with clinical benefits of Pexa-Vec (thymidine kinase-deactivated vaccinia virus plus GM-CSF) and cemiplimab (REGN2810; anti-PD-1) in metastatic or unresectable renal cell carcinoma (mRCC).
Authors: Merchan Jaime R. , Bae Woo Kyun , Kim Chan , Oh Sung Yong , Lee Hyo Jin , Park Kwonoh , Mar Nataliya , Pachynski Russell Kent , Beom Seung-Hoon , Carranza Lucia , Ma Seunghyun , Mathias Melissa Divya , Seebach Frank A. , Rha Sun Young
Published: June 2024

e14539

Background: This study explores the transformation of 'cold' tumour microenvironments into 'hot' ones in mRCC, focusing on the potential of Oncolytic Viruses (OVs) for personalized immunotherapy. Recognizing the variability in patient responses, the research underscores the necessity for reliable biomarkers. The objective is to examine the correlation between plasma cytokine/chemokine levels and the efficacy of Pexa-Vec and cemiplimab, proposing that these biomarkers could predict treatment outcomes and contribute to more personalized cancer treatment protocols. Methods: In this study, mRCC patients from the REN026 trial were categorized into three treatment groups: Pexa-Vec (Intratumoral and intravenous) and cemiplimab combination therapy (N=65), intravenous Pexa-Vec and cemiplimab combination therapy (N=54), and cemiplimab monotherapy (N=14). Blood samples were collected at baseline, during treatment, and at end of treatment (EOT) for analysis. Subsequently, the plasma samples underwent analysis using the Human Cytokine 96-Plex Discovery Assay through the Luminex 200 system. The statistical approach included the Mann–Whitney U-test or Wilcoxon signed-rank test, along with a Cox proportional hazards model. The False Discovery Rate (FDR) method was employed to control type I error. Results: During the follow-up period from June 2018 to February 2023, key outcomes were observed as follows (Table): In the Pexa-Vec and cemiplimab cohort, a lower baseline of MCP-3 or an increased rate of change in post-treatment levels of IFNβ, Eotaxin, IL-1α, and sFasL were associated with improved Progression-Free Survival (PFS). Specifically, a low baseline of MCP-3 or an increased level of Eotaxin and sFasL post-treatment correlated with enhanced Overall Survival (OS). In the intravenous Pexa-Vec and cemiplimab group, a rise in post-treatment levels of IFNβ, Eotaxin, IL-17F, and sFasL were indicative of better PFS, with elevated Eotaxin also suggesting improved OS. Within the cemiplimab monotherapy group, an increase in post-treatment IP-10 was linked to favourable PFS. Conclusions: Our findings suggest the potential utility of plasma cytokine and chemokine profiles in clinical benefits of mRCC patient to the combination of Pexa-Vec and cemiplimab, thereby aiding in future personalized treatment approaches.
Platelet-mediated circulating tumor cell evasion from natural killer cell killing via immune checkpoint CD155-TIGIT.
Authors: Sun Yun-Fan , Li Tong , Ding Lin , Wang Jiyan , Chen Chen , Liu Te , Liu Yu , Li Qian , Wang Chuyu , Huo Ran , Wang Hao , Tian Tongtong , Zhang Chunyan , Pan Baishen , Zhou Jian , Fan Jia , Yang Xin-Rong , Yang Wenjing , Wang Beili , Guo Wei
Published: June 2024

e14552

Background: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. The interaction between platelets and CTCs is the most extensively studied of all blood cells, and it is well known that CTCs are surrounded by platelets, which form microplots on their surface and play a crucial role in cancer metastasis. The precise mechanisms platelets employ to contribute to CTC immune evasion have not been fully elucidated. Our previous single-cell RNA sequencing data indicated high expression of platelet-related genes in CTCs. Here, our study demonstrated that platelet adhesion to CTCs is prevalent in multiple cancers and is indispensable for CTCs metastasis. Methods: CTC isolation was performed by our self-established ChimeraX-i120 platform. CTC-platelet adhesions were identified by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. The cytotoxicity of natural killer (NK) cells was assessed by the reduction in tumor cell numbers measured using the xCELLigence system. In vitro and ex vivo co-culture systems were established by using platelets and NK cells isolated from the peripheral blood of patients for direct or indirect co-culturing with cell lines and patient-derived organoids (PDOs). The effects of platelets and NK cells on metastasis and immune responses were investigated in vivo by utilizing mouse models. Results: Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. Conclusions: Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
Potential of near real-time detection of cancer and immuno-oncology failure, within weeks of initiating therapy.
Authors: Taub Floyd , Russo Matthew , Wright Suzin Mayerson , Henry Charles
Published: June 2024

e14555

Background: For most areas of internal medical practice, biochemical and/or clinical tests rapidly allow physicians to evaluate if a drug being administered has activity in that patient. Unfortunately, for most of oncology, measuring response is by imaging after delay of months. Methods: In 2018 the Trau lab published that the pan-cancer DNA methylation pattern (general hypomethylation with specific hypermethylation) resulted in physico-chemical alteration in purified circulating tumor DNA (ctDNA) as well as genomic DNA. Detecting these changes were not sequence dependent, but rather the epigenetic alterations resulted in altered binding to a specific electrode, easily and quickly measured by differential pulse voltammetry. In 2022 our group using the “aiElectrode” method showed significantly improved ability to cleanly separate cfDNA from people with cancer and those without, as well as anecdotal success in using the method to separate progression from regression. The improved method is used here. Results: Here we present analysis of samples from 18 cancer patients from 3 small series with cfDNA taken before and after treatment; 20 pairs could be analyzed. The Scripps Clinic Bio-Repository supplied samples from 8 lymphoma patients before and after treatment with chemotherapy and a bone marrow transplant; all showed initially clinical improvement and decrease in the ctDNA by the aiElectrode. Subsequently 2 relapsed and in both cases ctDNA analysis showed increased ctDNA. The Drammen Hospital in Norway supplied 18 samples from 7 patients (2 or 3 time points each) with NSCLC treated with pembrolizumab immunotherapy. One responded and 6 had progression. The aiElectrode ctDNA results were concordant for all but one of the 7 patients. The University of Colorado provided before and after therapy specimens from three patients. In total, 20 pairs of specimens were analyzed and 19 were concordant, generating an accuracy of 95%. Some of the post treatment samples from Drammen were as early as 2 weeks after therapy initiation. Conclusions: As IO may result in cures, but also may result in pseudoprogression or hyperprogression, a simple, rapid turnaround, inexpensive, blood test to aid clinicians in the early detection of failing IO, and thus individualized switching to an alternative therapy (which typically costs much less) may be beneficial, even life saving for that patient, while reducing direct as well as indirect costs. Unlike other ctDNA technologies, this can eventually be offered in a small, point-of-care device that is simple and inexpensive enough for use at every oncologist office visit to provide near real-time tracking of treatment response. [Table: see text]
Cytotoxic function of human natural killer cells is transiently inhibited by transforming growth factor beta (TGFβ).
Authors: Patel Anjali , Maiocco Giuseppe , Mirto Catherine , Torry Donald S. , Wilber Andrew
Published: June 2024

e14557

Background: Natural killer (NK) cells can eliminate early neoplastic cells, however, their efficacy as an adoptive therapy for solid tumors is limited. We have shown that NK cells recovered from human kidney tumors are CD56pos/CD16dim/neg, poorly cytotoxic, and produce vascular endothelial growth factor (VEGF). These features are analogous to human decidual NK (dNK) cells that support the development and growth of the placenta during implantation. Transforming growth factor beta (TGFβ) is found at high levels in the decidua and kidney tumor environment, and is known to convert peripheral blood NK (pNK) cells to dNK-like cells in vitro. We hypothesized that TGFβ-mediated inhibition of NK cell proliferation and function is transient and therefore reversible. Methods: pNK cells were isolated from healthy donors (HD) by negative selection or purchased from ATCC (NK-92; CRL-2407). RT-qPCR and flow cytometry were used to assess NK markers: CD56, CD16 NKp46, CD49a, CD69; TGFβ receptors R1, R2, R3; VEGF; and cytokines IFNγ, TNFα. NK cells were cultured for 4-5 days with proliferative cytokines IL2 or IL15 alone and in combination, and without or with TGFβ (2-5 ng/mL). Cytotoxic function of NK cells (effectors) was quantified by lysis of human K562 cells engineered to express firefly luciferase (targets). Statistics (ANOVA/t-test) were performed using GraphPad Prism with p≤0.05 considered significant. Results: pNK cells from HD were CD56pos/CD16pos and NK-92 cells were CD56pos/CD16neg as reported. Both expressed all three TGFβ receptors, required IL2 or IL15 to survive in culture and were potently cytotoxic against K562 targets. TGFβ treatment of NK cells cultured with IL2 or IL2 plus IL15 suppressed proliferation by 20% and potently inhibited cytotoxic ability (85% reduction; p≤0.05). TGFβ caused significant changes in CD49a (35% increase), CD69 (45% increase) and IFNγ (50% decrease) but had no effect on NKp46, VEGF, or TNFα. TGFβ-mediated changes in NK cell phenotype and function reverted to normal when NK cells were returned to standard culture conditions for 4-5 days. Conclusions: Despite differences in CD16 expression, pNK cells and NK-92 cells are potently cytotoxic and represent an effective anti-cancer therapy. TGFβ limits this potential by blocking the proliferative effects of IL2 and IL15 and quelling cytotoxic function. TGFβ caused increased expression of integrin CD49a, a marker of tissue resident immune cells, and the early lymphocyte activation marker CD69. Augmentation of these surface markers was concomitant with diminution of IFN-γ, a cytokine critical for cell-mediated responses to tumors. These collective changes are akin to dNK cells that are not cytotoxic and instead support the implant. Importantly, all alterations were restored if NK cells were no longer exposed to TGFβ. Thus, inhibition of TGFβ signaling could preserve NK function in the tumor environment.
An exhaustive pre-clinical study of a circRNA drug candidate (cmRNA1210) encoding IL-12sc for anti-tumor therapeutics.
Authors: Wang Shuhang , Yang Jiali , Wei Lixiang , Tan Yiling , Sun Jiaojiao , Wu Fan , Huang Lingkun , Ma Peiwen , Zhou Jiawei , Zhao Guo , Wang Yuning , Tang Qiyu , Zuo Chijian , Li Ning
Published: June 2024

e14569

Background: Circular RNA as emerging technology hasn't been approved of acceptance of any IND application. What’s the pharmacokinetics, pharmacodynamics and toxicity study of circular RNA drug candidate would be like is still unpublished. Here we provide an exhaustive pre-clinical study of a novel circular RNA drug candidate encoding IL-12sc, the immune stimulatory effector. Methods: Here, we performed an exhaustive pre-clinical study of a circular RNA drug candidate(cmRNA1210) encoding IL-12sc, including pharmacokinetics, pharmacodynamics, pharmacology and toxicology study. Meanwhile, we explored the bioactivity and cross reactivity of cmRNA1210 in vitro and the pharmacokinetics in vivo. Results: cmRNA1210 and its replace molecule exhibits robust therapeutic effect and good safety in syngeneic mouse tumor model and humanized human tumor mouse model. In situ administration of cmRNA1210 achieves abscopal effect and inhibits lung metastasis progression. Treatment with cmRNA1210 leads to cytokines change in plasma and tumor, cytotoxic immune cells accumulation in tumor and tumor tissue necrosis. Dynamic transcriptome profiling of tumor tissue post cmRNA1210 treatment. Combination with checkpoint inhibitor exhibits synergy effect and significantly decreases tumor relapse rate. Kaplan-Meier survival curve in TCGA dataset shows strong correlation of high IL-12A/B expression and long survival. Conclusions: The bioactivity and cross reactivity in rodents and primates of cmRNA1210 were validated in vitro. The advantage of pharmacokinetics of circular RNA was confirmed in vivo. cmRNA1210 exhibits robust anti-tumor effect in various tumor models, indicating its wild application situation in clinical. In situ treatment achieves abscopal effect and significantly inhibits lung metastasis progression. Systemic anti-tumor effect has been successfully initiated. The pharmacodynamics study reveals there are cytokine changes, immune cells activation or accumulation at tumor site and tumor tissue necrosis after cmRNA1210 treatment. cmRNA1210 as immune stimulatory effector works synergistically with checkpoint inhibitor. Kaplan-Meier survival analysis of IL-12 expression based on TCGA dataset shows there is a strong correlation of high expression and long survival. Overall, this pre-clinical study provides elaborate results of cmRNA1210 as anti-tumor therapeutics and demonstrates the great potential to enter clinical trial in the future.
Therapeutic potential of immune-cold solid tumors through homologous recombination deficiency.
Authors: Shafi Gowhar , Ramesh Aarthi , D'Souza Alain , Prajapati Sangeeta , Jadhav Bhagwat , Hariramani Kanchan , Basavalingegowda Madhura , Jadhav Vikas Leelavati Balasaheb , Kothavade Hrishita , Mobeen Fauzul , Bharde Atul , Khandare Jayant
Published: June 2024

e14585

Background: Genome-wide homologous recombination deficiency (HRD) score is an important parameter to select patients for HRR pathway inhibitors. HRD scores are independent therapeutic predictors unlike tumor mutation burden (TMB), and microsatellite instability (MSI) values to stratify tumors for predicting immunogenicity. Since solid tumors often choose the hallmark of immune evasion to disseminate to distant tissues, their identification and treatment through genomic signatures for immunotherapy is essential. Low TMB and MSI values are often associated with immune evasion and immune cold tumors. For such patients HRD scores can be important determinants to inform on the therapeutic potential of HRR pathway inhibitors and immune checkpoint inhibitors (ICI). In this study, we retrospectively investigated solid tumors with metastatic phenotypes exhibiting microsatellite stable (MSS), MSI-Low and TMB low phenotypes. The presence of HRR pathway deficiency in these patients may lead to chromosomal instabilities and cell surface neo-antigens thereby offering potential therapeutic benefit to PARP inhibitors and ICI. Methods: 53 metastatic cancer patients were retrospectively analysed for genome-wide HRD, TMB and MSI scores based on OncoIndx comprehensive gene panel (CGP). OncoIndx CGP targets 1080 cancer related genes along with 47 HRR genes and 1600 MSI signature sites. HRD, TMB and MSI scores were determined by sequencing the individual sample libraries in pair end mode on Illumina Nextseq platform (depth 5500X). Cutoff scores HRD high (≥50), TMB high (≥10 Mutations/MB), MSI high (≥20). Results: A cohort of 53 solid tumor patients were evaluated retrospectively of which 71.6% (n=38) patients showed metastasis (brain, Popliteal fossa, skeletal, and nodal metastasis). Of these, 9.4% (n=5) patients were detected with MSI-high, 56.6% (n=30) were MSI-Low and 1.8% (n=1) were MSS. 13.2% (n=7) patients were TMB-High, 3.7% (n=2) were TMB intermediate and 41.0% (n=22) were TMB-Low. Most importantly, 41.0% (n=22) patients were both MSI and TMB low thus transforming the tumor suggestively immune-cold. Only 22.7% (n=5) patients showed PD-L1 expression on IHC with scores ranging from TPS: 2% to 20%. In this dominantly immune-cold patient cohort, 40.9% (n=9) patients showed high/intermediate HRD (22.7% high (n=5); 18.18% Intermediate (n=4)). Conclusions: The presence of HRD in 40.9% patients in the dominant immune-cold patients was observed with increased chromosomal instability and cell surface neo-antigens. Thus, HRD could potentially transform tumors to become immune-hot to benefit from PARP inhibitors and ICI.