bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in the management of small HER2-positive breast cancers.
Authors: Mueller Carolin , Rahul Rangan , Kruse Megan Lynn , Alhilli Zahraa
Published: July 2024

e12523

Background: Small HER2 positive breast cancers have not been well studied in randomized trials. The treatment landscape for this population aims to optimize efficacy while minimizing potential over-treatment and associated toxicities. Due to the potential for post-neoadjuvant therapy optimization, use of neoadjuvant systemic therapy (NAT) increased in recent years. However, this approach can often lead to overtreatment of patients with small tumors. This study aims to evaluate recent trends in treatment patterns of patients with T1 HER2 positive tumors. Methods: Patients diagnosed with HER2 positive, T1, any N, breast cancer treated at a single institution from January 2018 to December 2022 were included. Clinicopathological data, treatment data, and survival data were collected and analyzed. Results: 326 patients were included. Mean age was 62 (±12.2) years. T category included 3 (0.9%) cT0, 17 (5.2%) cTmi, 28 (8.6%) cT1a, 94 (28.8%) cT1b, 178 (54.6%) cT1c tumors, and 6 patients (1.8%) had clinical T1 stage without further specification. 41 patients (12.6%) had cN+ disease and 243 (74.5%) were hormone receptor positive. Systemic therapy data was available for 288 patients; 7 (2.4%) received Herceptin monotherapy, 105 (36.5%) Taxol + Herceptin, 41 (14.2%) Taxol + Carboplatin + Herceptin, and 74 (25.7%) Taxol + Carboplatin + Herceptin + Pertuzumab (TCHP), 12 (4.2%) other. 49 patients (17%) did not receive any systemic therapy. 58 patients (17.8%) were treated with NAT and a pathologic complete response rate was noted in 39 patients (67.2%) undergoing NAT. Overall, in patients who received systemic therapy, NAT increased from 2018 (17.6%) to 2021 (37.5%) and decreased in 2022 (23.5%). Similar patterns were observed in patients with T1a/b (2021: 17.4%; 2022: 0%), as well as T1c (2021: 51.4%; 2022: 36.4%). TCHP was the most commonly administered NAT regimen (86.2%). Discontinuation or dose reduction occurred in a total of 57 patients (18.8%). Conclusions: The primary treatment for T1 HER2 positive breast cancers is surgery with adjuvant HER2 targeted therapy in combination with chemotherapy. Although NAT witnessed an upward trend from 2018 to its peak in 2021, its utilization declined again in 2022. A balance between the most effective treatment and minimizing toxicities should be ensured.
Examining a genomic test in predicting extended endocrine benefit and recurrence risk in a diverse breast cancer population.
Authors: Lee Ho Hyun , Siu-Li Nicholas , Pagano Ian , Fukui Jami Aya
Published: July 2024

e12526

Background: Extending adjuvant endocrine therapy (EET) beyond five years for early-stage hormone receptor-positive (HR+) breast cancer reduces late distant recurrence risk. The genomic test, Breast Cancer Index (BCI), has prognostic value and predicts the benefits of prolonged therapy, yet no studies have explored this testing in a diverse population. This study assesses late distant recurrence risk and predictive benefits of EET to better understand its relevance in a diverse early-stage HR+ breast cancer population. Methods: We analyzed patient demographics, clinical and pathologic characteristics, and BCI scores of 150 women in Hawaii with early-stage HR+ breast cancer, self-identifying as White, Filipino, Japanese, Native Hawaiian, or other. Tumor characteristics examined include size, grade, histology, lymph node, and ER/PR/HER2 receptor status. Logistic regression analyses used race, distant recurrence risk, and tumor features as predictor variables. BCI prediction of benefit and distant recurrence risk served as outcome variables. Results: Japanese patients had significantly lower odds of having a high risk for distant recurrence (OR = 0.02, p < 0.0001) compared to White. Other Asian PIs also showed reduced odds of high distant recurrence risk (OR = 0.07, p = 0.02), albeit to a lesser extent than Japanese. Patients with high distant recurrence risk had significantly greater odds of a score predicting benefit than those with low risk (OR = 5.03, p = 0.009). Racial or ethnic differences in predicting benefit with EET were not statistically significant. Conclusions: Results show no racial or ethnic differences in predicting the benefit of EET, strengthening BCI’s universal applicability in diverse women with early-stage HR+ breast cancer. Patients with higher distant recurrence risk were predicted to benefit from EET. This suggests potential variations in tumor features or other factors affecting distant recurrence risk among racial groups. Limitations include a relatively small sample size and lack of data from patients representing other racial groups. Future studies should expand the sample size and adjust for known breast cancer risk factors to better understand the racial and ethnic implications of BCI.
De-escalation of breast cancer surgery using vacuum-assisted biopsy (VAB): Interim results.
Authors: Krivorotko Petr , Amirov Nikolay , Mortada Viktoriia , Emelyanov Alexander , Yereshchenko Sergey , Pesotskiy Roman , Tabagua Tengiz , Artemyeva Anna , Zhiltsova Elena , Gigolaeva Larisa , Bondarchuk Yana , Enaldieva Diana , Ulrikh Daria , Levchenko Valerii , Krzhivitskiy Pavel , Busko Ekaterina , Semiglazova Tatiana , Novikov Sergey , Semiglazov Vladimir
Published: July 2024

e12590

Background: Currently, there is a point of view according to which, in patients diagnosed with breast cancer (BC), surgical intervention when achieving a complete pathological response (pCR) after neoadjuvant systemic therapy (NST) is diagnostic, not therapeutic, and does not affect long-term treatment outcomes. Vacuum-assisted biopsy (VAB) of the tumor bed in breast cancer has shown promising results as a minimally invasive method for diagnosing pCR. This work presents a prospective analysis of treatment of patients with triple-negative and HER2-positive breast cancer who achieved pCR after NST and who underwent VAB alone without subsequent breast surgery. Methods: Women aged 18 years old and older with unicentric (cT1-2N0-1M0) triple-negative or HER2-positive breast cancer were included. Primary lesions were marked with a single clip before NST. In cases with nodal involvement (cN1) the affected lymph nodes were also clipped. Patients with TNBC received 4 cycles of AC q21d followed by 12 cycles of weekly paclitaxel and carboplatin AUC 2.0. HER2+ patients received dual anti-HER2 blockade with chemotherapy (TCHP or AC-DHP regimen). Breast US, mammography and mammolymphoscintigraphy were used at baseline and at response evaluation. Patients with complete clinical response after NST underwent VAB with 7G needle and US-guidance simultaneously with the sentinel lymph node biopsy and/or targeted axillary dissection. In case if no invasive or in situ residual tumor cells were detected (ypT0N0), no further breast surgery was performed and patients underwent subsequent radiation therapy. Primary endpoint was 2-year ipsilateral breast tumour recurrence-free survival [IBTR-FS]. Secondary endpoints included 2-year disease-free survival (DFS) and complication rates. The study is registered on сlinicaltrials.gov, NCT04293796. Results: 35 patients with a mean age of 48.3 (31–67) years were included in the trial. Examination of VAB samples showed that 11 (31.4%) patients had a residual tumor, and in 24 (68.6%) patients no tumor cells were detected (ypT0N0). This 24 patients were included in the analysis. Median follow-up was 26 months. Median survival was not reached for any endpoint. 2-year IBTR-FS was 91.7% in the VAB group. 2-year DFS was 83.3% in the VAB group. We registered 4 events: in 2 patients biopsy-proven de novo breast cancer occurred in contralateral breast, in 1 patient recurrence occurred in the postoperative zone and in 1 patient recurrence occurred in another quadrant of the ipsilateral breast. Conclusions: Additional observation and large randomized prospective studies are needed to determine the safety of VAB use. Clinical trial information: NCT04293796 .
A retrospective, single-center study comparing two neoadjuvant protocols for patients with HER2-positive breast cancer.
Authors: Itay Amit , Globus Opher , Levanon Keren , Sella Tal , Bernstein-Molho Rinat , Shapira Rotenberg Tal , Oedegaard Cecilie , Fourey Dana , Gal-Yam Einav Nili
Published: July 2024

e12623

Background: Neoadjuvant treatment is common in Stage 2+3 HER2 positive tumors. Cytotoxic and anti-HER2 drug combinations are used. Pathological complete response (pCR) correlates with improved survival and decreased risk of relapse. Trastuzumab may cause temporarily congestive heart failure (CHF) while anthracyclines may cause irreversible CHF. Current guidelines advise non-anthracycline based regimens. Here, we compare the efficacy and toxicity of these two regimens. Methods: Retrospective data were collected on 179 patients with clinical stage II-III, who received neoadjuvant treatment with either 6 cycles of DCHP (Docetaxel, Carboplatin AUC6 [53.2% received AUC5], Trastuzumab, Pertuzumab) or ACTHP (doxorubicin, cyclophosphamide followed by weekly Paclitaxel combined with HP). According to pCR response post surgery, adjuvant HP or TDM-1 were given to go complete one year of treatment. Efficacy Indices of pCR were evaluated in both cohorts and according to HER2 IHC staining (3+ or 2+ FISH positive), hormone receptor (HR) and nodal status. Toxicity indices were reductions in left ventricular ejection fraction (LVEF), dose reductions, hospitalizations and febrile neutropenia. Results: Between 9.2017 and 6.2022, 106 patients received ACTHP and 73 received DCHP. Median age at diagnosis, HR status, HER2 IHC (2+FISHpos or 3+) and nodal status were balanced. PCR occurred in 63.1% of all patients, numerically higher in the ACTHP group at 67.0% vs. 57.5% in the DCPH group (p=0.129). Symptomatic LVEF decrease (>10% or LVEF≤50%) was observed in 6.6% of the ACTHP group vs. 0% in the DCHP group (p<0.001). Hospitalization rates were similar (14%). Dose reductions occurred more often in the DCHP regimen vs ACTHP (54.8% vs 24.5% respectively) (p<0.00001) mostly due to asthenia and diarrhea. Febrile neutropenia was slightly higher in the ACTHP group but not statistically significant. Conclusions: In this study, pCR rates were numerically better in the ACTHP regimen vs. DCHP, though not statistically significant. Dose reductions were more common in the DCHP but had less cardiotoxicity. pCR rates were relatively low in both regimens where Her-2 +2, FISH pos. This study shows that the DCHP is a safe and effective alternative to anthracycline based chemotherapy though total dosage may be an important factor in the level of pCR.[Table: see text]
Retrospective analysis of factors impacting efficacy of patients with later stage breast cancer receiving neoadjuvant therapy.
Authors: Wang Nan , Zhu Anjie , Ran Ran , Yan Ying , Shao Bin , Liang Xu , Jiang Hanfang , Song Guohong , Di Lijun , Li Huiping
Published: July 2024

e12624

Background: Neoadjuvant treatment is the current standard of care for patients with early breast cancer (EBC), especially for patients with later stage breast cancer (LBC). We conducted this retrospective study to summarize the correlation between pathologic complete response (pCR), disease-free survival (DFS), overall survival (OS) and clinical impacting factors of patients with later stage received neoadjuvant treatment. Methods: We retrospectively analyzed the clinical data of patients receiving neoadjuvant treatment at the Department of Breast Oncology, Peking University Cancer Hospital from Jan. 2013 to Feb. 2022. Statistical analyses were carried out using IBM SPSS Statistics. We calculated pCR rate, DFS and OS. Pearson’s χ2 or Fisher’s exact tests were used for comparison of categorical variables. DFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox regression was used to identify factors impacting on survival. All p values were two sided and p<0.05 was considered to denote statistical significance. Results: Of 198 patients, most of them were in stage II (115/198, 58.1%), followed by stage III (79/198, 39.9%) and stage I (4/198, 2.0%), The pCR rates for different molecular subtypes were 31.6% TNBC, 29.7% for HR-Her2+ BC, 26.1% for HR+Her2+ BC and 1.3% for HR+Her2- BC, respectively (p=0.000). The median DFS of patients with or without pCR was 59.63 months (95%CI: NA-NA) and 29.83 months (95%CI: 21.31-38.35), respectively (p=0.012). DFS of patients who were cT1 [59.63 months (95%CI: 37.95-81.31)] or cT2 [39.56 months (95%CI: 24.19-54.93)] was significantly longer than that of patients who were cT3-4 [25.76 months (95%CI: 14.11-37.41), p=0.041]. Miller Payne (M-P) grade and ypTNM stage were also significantly associated with DFS in univariate analysis and in the multivariate cox regression model after adjusting for molecular subtypes. The 5-year OS were 87.0% for patients who reached pCR and 52.0% for patients who didn’t (p=0.009). Conclusions: The pCR was significantly associated with molecular subtypes. HR negativity and overexpression of Her2 were significantly associated with higher pCR rate. Patients reached pCR had longer DFS and OS. DFS was significantly associated with cT stage (T1 vs T2 vs T 3-4), ypTNM stage and M-P grade.
Prediction of brain metastases of breast cancer using next generation sequencing genomics.
Authors: Hunting John , Ormond Sean , Wang Yuezhu , Liu Liang , Xing Fei , Chan Michael D. , Ruiz Jimmy
Published: July 2024

e14004

Background: Breast cancer was the most common malignancy diagnosed in 2023 with over 300,000 new diagnoses. Though it is highly treatable when caught in early stages, metastatic disease is highly morbid. Approximately 0.4% of all cases and 7.2% of cases of metastatic breast cancer will develop brain metastases. Hormonal receptors correlate poorly with risk of brain metastasis. Predictive factors for breast cancer brain metastases remain elusive. This project aimed to identify genomic risk factors for the metastasis of breast cancer to the brain. Methods: We created a retrospective cohort of all breast cancer patients with next generation sequencing (NGS) at a comprehensive cancer center and its associated clinics. All NGS in the cohort was performed by FoundationOne. Brain metastases were defined via ICD-10 codes. Univariate analysis was performed using Fisher’s Exact test. Significance was defined as p<0.05 after adjustment of multiple testing corrections performed using the Benjamini-Hockberg procedure. A multivariable logistic regression model was fit; to avoid overfitting, the maximum number of covariables was defined by requiring 10 cases for every variable included. Model fit was compared by the Akaike information criterion (AIC) statistic. SAS v9.4 was used for all analyses. Results: This final cohort included 242 patients, of which 29 (12%) developed brain metastases. Among the standard panel of 223 tested genes, 11 were significantly associated with brain metastases after multiple testing correction. Significant genes included: TP53, GATA3, PIK3CA, EP300, MSH3, NTRK1, BRCA1, CBFB, FGFR4, MAP2K2, and NOTCH2. TP53 was the most prevalent gene mutation amongst brain metastases patients. The gene was present in 79% (23/29) of all brain metastases cases and 96% (23/24) of patients with TP53 had brain metastasis. PIK3CA and GATA3 were the next most common in 10 (34%) and 6 (21%) cases respectively. In building predictive models, the optimal model included TP53, GATA3, and CBFB which presented an AIC of 33.15 and an AUC of 0.98. The best two variable model included TP53 and PIK3CA with AIC of 49.67 and AUC of 0.95. Conclusions: Among this cohort, 11 genes were found to be significantly associated with the development of brain metastases. Among them, TP53 was the most prevalent while GATA3, PIK3CA, and CBFB also contributed to predictive ability. These variables suggest high levels of predictability, though given the limited sample thorough validation will be required. However, given the numerous genes found to be associated and the significant starting predictivity, there is potential for NGS to identify those at higher risk of brain metastases. Further study and expansion of NGS will be needed to validate these results and investigate the timing of brain metastases for the potential of early detection.
Effect of the timing of recurrence on survival among patients with breast cancer with brain metastasis.
Authors: Miller Kendall , Strawderman Myla S. , Niraula Sujan , Babbra Ramandeep , Neupane Niraj , Shrestha Asis , Gouli Sugam , Kharel Zeni , Anders Carey K. , Mohile Nimish , O'Regan Ruth , Falkson Carla Isadora , Weiss Anna , Magnuson Allison , Stanford Sarah , Dhakal Ajay
Published: July 2024

e14005

Background: Patients with Metastatic Breast Cancer (MBC) and brain metastasis (BM) have poor prognosis. There is a lack of data on the effects of timing of MBC diagnosis [de novo (d) vs recurred (r) MBC] and BM diagnosis [dBM vs later onset (lo) BM] on overall survival (OS). We conducted a natural history-type study to investigate these effects among MBC BM patients. Methods: The data for this retrospective single institute study was extracted from a database of MBC BM patients diagnosed with BM from Jan 2010 to June 2021. Definitions: dMBC= MBC at initial diagnosis (Dx); rMBC= MBC with prior history of early stage BC; dBM= BM diagnosed< 6 weeks (wk) from MBC Dx; loBM= BM diagnosed ≥ 6 wk from MBC Dx. The following endpoints were compared between dMBC vs rMBC: 1. interval from MBC to BM Dx (Interval MBC-BM) 2. OS from MBC Dx 3. OS from BM Dx. OS from BM Dx was compared between dBM vs loBM. Median endpoints were estimated using the Kaplan-Meier method and reported with 95% confidence intervals (CI). Cohorts were compared using the Logrank test and adjusted for other variables using Cox models. Results: Interval MBC-BM, OS from MBC Dx, and BM Dx were not statistically different between dMBC and rMBC groups in unadjusted analyses (See Table) and when adjusted in multivariate analyses. Median OS from BM Dx was significantly longer in dBM group vs loBM group (See Table). In multivariate model adjusting for variables at BM Dx (age, race, performance status, visceral disease, number of BM >1cm, leptomeningeal disease, BC receptor types), risk of death was higher in loBM group vs dBM group (Hazard Ratio, HR = 0.499; p=0.006). In dMBC group, 28.1% had dBM compared to 45.6% in the rMBC (p=0.083, Chi-square test). Subset analyses: Among rMBC group, median OS from BM Dx with dBM (n=42, OS=44.3 months (m), 95% CI 19.0-Not evaluable (NE)) was significantly longer compared to loBM (n=50, OS=13.7m (6.6-21.4)), p=0.002 (LogRank Test); but among dMBC group, there was no significant difference in OS from BM Dx with dBM (n=9, OS=32.4m (12.9-122.5)) vs. with loBM (n=23, OS= 17.8m (6.6-NE)), p=0.885. Conclusions: In a retrospective database of patients with BM from BC, time from MBC to BM diagnosis, OS from MBC diagnosis, and OS from BM diagnosis did not differ between those with recurrent vs de novo MBC. Interestingly, in unadjusted and adjusted analyses, OS from BM diagnosis was longer for those with de novo BM diagnosed at/around MBC diagnosis than those whose BM was later in onset. Earlier-onset BM in the MBC disease course could be more sensitive to cancer-directed therapies. Studies are needed to test this hypothesis.[Table: see text]
Assessment of CDKN2A homozygous and hemizygous deletion status in gliomas.
Authors: Li Hainan , Fan Chongzhu , Dai Lijun , Li Zhi , Luo Ningning , Zhang Xing , Ye Lei , Han Tiantian
Published: July 2024

e14021

Background: Homozygous deletion of CDKN2A (Homdel) has been included in the WHO CNS5 classification as a grade 4 definition in IDH mutated gliomas without the 1p-/19q-codeletion ( IDH mu-noncodel). Hemizygous CDKN2A deletion (Hemdel) has also been reported to be associated with poor prognosis. The identification methods for CDKN2A deletion include next generation sequencing (NGS), methylation array, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). However, at present, there is no gold standard threshold for FISH to judge the homozygous and hemizygous deletion. Methods: We collected formalin fixed paraffin-embedded (FFPE) tissue samples from 99 patients with adult-type diffuse glioma and all samples were tested using DNA-based NGS profiling (Simceredx). In addition, CDKN2A status was also detected by FISH and IHC (P16 and MTAP). Based on the CDKN2A status determined by NGS, the FISH were evaluated using ROC curves, including Area Under Curve (AUC), sensitivity, specificity, and cut-off values of Homdel and Non-Homdel, and deletion (Homdel and Hemdel) and non-deletion. The consistency of CDKN2A status identified by NGS, FISH IHC-P16 and IHC-MTAP was compared by Kappa test and Cramer V coefficient. Results: In 99 enrolled patients, NGS results showed 49 patients with CDKN2A Homdel, 18 patients with CDKN2A Hemdel, and 32 patients with CDKN2A Normal. There were no significant differences in age, gender, location of occurrence, IDH mutation status, or receiving chemoradiotherapy among the three groups. There were statistically significant differences in cancer subtype (p value=0.015) and grade (p value=0.010) among the three groups: oligodendroglioma and 2-3 grade was more likely to be normal in CDKN2A and grade 4 significantly predisposed to be Homdel. The ROC curve determines that cutoff of Homdel and Non- Homdel by FISH is 23%, and greater than 23% is Homdel. The ROC curve showed that the AUC of FISH method using 23% cutoff is 0.958, and the sensitivity and specificity were 85.11% and 100%, respectively. The consistency between FISH and NGS was 0.854. For the inconsistent samples, all NGS results were Homdel, and all FISH were deletion except one. Compared the results with FISH, we found that the results of NGS and IHC-P16 were more consistent. The ROC curve determines that the cutoff of deletion and non- deletion by FISH is 39%, and greater than 39% is deletion. The ROC curve showed that the AUC of FISH method with 39% cutoff is 0.962 and the sensitivity and specificity were 95.31% and 90.62%, respectively. Consistency comparison of the four methods showed that the consistency between FISH and NGS in determining Homdel and Non-Homdel, and deletion and non-deletion were the highest, 0.841 and 0.86, respectively. Conclusions: In our study, four methods were used to determine the status of CDKN2A, and results showed that the consistency between FISH and NGS was the highest.
The role of neoadjuvant clinical trials in patients with newly diagnosed glioblastoma.
Authors: Bazer Danielle A. , Grossman Stuart A.
Published: July 2024

e14022

Background: Novel cytotoxic drugs are commonly first studied in patients with solid tumors who have recurrent disease. If high response rates and durable remissions are observed, further studies are conducted in previously untreated cancers where the novel agent can be combined with radiation or administered as neoadjuvant therapy (NAT) to reduce tumor size before surgery or radiation and to limit systemic dissemination. While NAT can provide critical information on response rates and survival in previously untreated patients, it can add toxicities and delay the administration of standard therapies. Neoadjuvant chemotherapy is now standard-of-care in many systemic cancers but is rarely considered in patients with glioblastoma (GBM). This literature review was conducted to describe factors leading to NAT playing an increasingly important role in systemic cancers and a diminishing role in patients with GBM. Methods: Prospective trials published between 1980 and 2023 where patients with newly diagnosed systemic cancers and GBM received NAT prior to radiation were identified in PubMed. Results: During these 43 years, over 5,000 NAT trials in patients with systemic cancers were published. As a result of these studies, NAT is now considered standard therapy for 28 different cancers. In contrast, during the same years only 51 prospective studies were reported evaluating the efficacy of NAT in newly diagnosed GBM. These clinical trials accrued a total of 2,047 patients and evaluated the efficacy of nitrosoureas, temozolomide, platinum-based agents, and targeted therapies. These studies peaked before 2005, when combining temozolomide and radiation was shown to improve survival, and declined thereafter. NAT temozolomide was studied in 12 trials (641 patients) resulting in a median response rate of 35% (range 8.7-51%) and a median overall survival of 12.5 (range 6-22) months. NAT trials in patients with GBM were not associated with unexpected toxicities, major reductions in survival, or poor patient accrual. Conclusions: As in other solid tumors, NAT in patients with GBM is relatively safe and feasible. Enthusiasm for this approach has been limited by the paucity of active agents in recurrent glioblastoma that could be subsequently evaluated in newly diagnosed patients. However, the neoadjuvant setting is ideally suited to rapidly screening novel cytotoxic agents for efficacy as it allows: 1) radiographic response rates in previously untreated patients to be the primary endpoint, 2) small sample sizes, and 3) efficacy results in 2-3 months when patients are transitioned to standard care. Given the well documented safety and feasibility history of using NAT in patients with solid tumors and GBM, this approach has the ability to rapidly identify potentially active, novel cytotoxic agents, especially in patients with MGMT unmethylated, IDH wildtype GBM who are unlikely to benefit from temozolomide.
Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma: Preliminary efficacy and mechanism as a monotherapy.
Authors: Huang Ruofan , Zheng Anjie , Xu Yuhong , Zhang Xiaochen , Wu Jinsong
Published: July 2024

e14030

Background: The absence of I.O success in advanced glioma treatment suggests that a deeper understanding of the brain tumor and the immune microenvironment is critical. It is well-documented that refractory/recurrent glioma has an immunosuppressive nature. One frequent observation is the high level of circulating myeloid-derived suppressor cells (MDSCs). We conducted a exploratory study to assess an immunomodulatory approach for relieving immune suppression employing HF1K16, a liposome all-trans retinoic acid (ATRA) suspension. Methods: This Phase I study (NCT05388487) comprise a conventional 3+3 dose escalation plus an advanced glioma-specific expansion arm. Eligible patients had prior confirmed advanced solid tumor and failed standard treatment. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. Survival data were calculated as it is difficult to determine the timing of progression for immunotherapies owing to pseudoprogression. Results: As of Feb 2th, 2024, 14 recurrent/refractory glioma patients including 6 males and 8 females had been enrolled in this study. 2 of them withdrew before finished 1st cycle. 7 had received treatment for at least 3 cycles and 1 had achieved CR after 15 cycles. For the 8 primary diagnosed grade IV glioma patients, the mOS is 7.8m, and 6 (75%) are alive. The mOS for the primary dignosed grade II/III is 13.7m and 100% patients are alive (n=4). There is 1 recurrent GBM patent who had received 5 cycles of treatment. MRI showed an enlargement of tumor lesion while KPS score remained >90. A surgical resection was performed and we subsequently studied the posttreatment tumor specimens (window of opportunity). IHC and flow cytometry analysis revealed prominent perivascular and intratumoral inflammatory infiltrate, containing CD8+CTL cells and HLA-DR expressing cells. Conclusions: While the interpretation of our data is limited by the small sample size, the results provide an encouraging signal and warrants further assessment. Patient recruitment continues with anticipated completion in 2024. Clinical trial information: NCT05388487 . [Table: see text]
Immunotherapy-based therapy versus chemotherapy for the neoadjuvant treatment of locally advanced dMMR/MSI-H gastric cancer.
Authors: Zhang Pengfei , Gou Hongfeng
Published: July 2024

e16121

Background: Growing evidences have suggested that immunotherapy represents a promising treatment for the neoadjuvant treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer. The study aimed to compare the efficacy of neoadjuvant chemotherapy and immune checkpoint inhibitor (ICI)-based therapy in locally advanced, dMMR/MSI-H gastric cancer. Methods: Patients with MSI-H/dMMR locally advanced gastric cancer who received neoadjuvant chemotherapy, or ICI-based therapy between December 2018 and June 2023 at West China Hospital, Sichuan University were included. Patient data were collected from the prospectively database program of gastric cancer at our Hospital. Demographic and clinicopathologic data of patients were collected, including age, sex, ECOG performance status, primary tumor site, tumor staging, Lauren’s classification, tumor response, tumor regression grade (TRG), R0 resection, disease-free survival (DFS) and overall survival (OS). Results: A total of 21 patients treated with ICIs-based regimens and 18 patients treated with chemotherapy were included. In the ICI-based therapy group, 10 patients (47.6%) received dual PD-1 and CTLA-4 blockade, 1 patient (4.8%) received PD-1 blockade, and 10 patients (47.6%) received PD-1 blockade combined with chemotherapy. The median age of chemotherapy group and ICI-based group were 63 years (range, 36-76 years) and 59 years (range, 34-74 years), respectively. The rates of T4b and limited metastases were significantly higher in the ICI-based therapy group compared to chemotherapy group (T4b: 11.1% vs. 23.8%; limited metastases: 0% vs. 19.0%). 17 patients (94.4%) in the chemotherapy group and 20 patients (95.2%) in the ICI-based therapy group underwent R0 radical gastrectomy. One patient in the chemotherapy group did not undergo surgery due to disease progression. One patient in the ICI-based therapy group refused radical gastrectomy. For patients undergoing surgery, TRG 0-1 rate was obviously lower in patients receiving chemotherapy compared to those treated with ICI-based regimen (0.0% vs. 78.9%). The pCR rates in the chemotherapy group and ICI-based group were 0.0% and 57.9%, respectively. The pCR rates in patients treated with dual PD-1/CTLA-4 blockade and PD-1 blockade with chemotherapy were 66.6% and 50.0% (P = 0.65). Median DFS and OS have not yet been achieved due to the short follow-up time. Conclusions: Improvements in TRG 0-1 rate and pCR rate suggested that ICI-based treatments are favorable in the neoadjuvant setting of locally advanced, dMMR/MSI-H gastric cancer compared to chemotherapy. However, within the overall favorable group, there was no differences between dual PD-1/CTLA-4 blockade and PD-1 blockade with chemotherapy in term of pCR rate. Whether high pCR rates can translate into long-term survival benefits requires longer follow-up time.
Incidence and demographics of bile duct cystadenocarcinoma from the National Cancer Database.
Authors: Demangone Michael , Abi Karam Karam Rabih , Lee Daniel , Langland Dylan , Hsia Beau , Rossi Anthony , Heise Craig , Silberstein Peter T.
Published: July 2024

e16231

Background: Bile duct cystadenocarcinoma, a rare tumor of the biliary tree, manifests itself within both multilocular and unilocular cysts composed of mucous-secreting, cytologically malignant epithelial cell populations. While similar in presentation to other biliary tree malignancies, bile duct cystadenocarcinoma has unique morphological variations between sexes. This contrast in disease manifestation based on sex could potentially impact diagnostic imaging, testing approaches, and treatment strategies for both female and male patients. The potential impact of demographics on the prognosis of bile duct cystadenocarcinoma, along with limited literature on the subject, make it a compelling subject for hypothesis generating epidemiological inquiry. The National Cancer Database will be used to illuminate the demographic intricacies. In this pursuit, we aim to provide a demographic and incidence background to prompt future research dedicated to the understanding of bile duct cystadenocarcinoma. Methods: The National Cancer Database (NCDB) was used to complete a retrospective cohort analysis of all patients diagnosed with histologically confirmed bile duct cystadenocarcinoma from the years 2004 to 2020. Demographic factors were subjected to descriptive statistical techniques, while a comprehensive regression analysis was employed to analyze the patterns in disease incidence. Results: Between 2004 and 2020, 64 patients were diagnosed with bile duct cystadenocarcinoma in the NCDB. There was a decline of incidence per year (R2 = 0.0392). The majority of those diagnosed with this disease were female (70%). Most of the patients were from Caucasian ethnicity (73%). The average age of diagnosis was 65 years old ( SD = 12.5, range = 33-88). The highest percentage of patients were on Medicare (55%). The primary site of the cancer was in the intrahepatic bile duct (63%). 70% of patients had a Charlson-Deyo Score of 0. Stage 1 was the most detected stage (42%). The average size of the tumor when detected was 65 mm (SD = 35.5, range = 9-144 mm). Most patients (72%) received surgical treatment and the remainder received radiation or chemotherapy alone. Regarding margins post-surgery, most of the patients (56%) had no residual tumor. Almost all patients (92%) received treatment designed for cure/remission. Mean survival after diagnosis was 8 years. Conclusions: Consistent with a vast majority of case reports, our results demonstrated that the majority of cases of bile duct cystadenocarcinoma were found in women (70%). Moreover, given that a significant proportion of patients affected by this disease are covered by Medicare (55%), we contend that investigating the precise influence of demographic factors and social determinants of health in this context presents a compelling avenue for future research.
Nodular number as a prognostic indicator in hepatic resection for intermediate-stage hepatocellular carcinoma: An international multicenter observational study.
Authors: Liu Han , Fan Zhong-Qi , Wang Ming-Da , Serenari Matteo , Schwartz Myron , Chen Zhong , Zhou Ya-Hao , Wang Xian-Ming , Chen Ting-Hao , Li Jie , Zhang Cheng-Wu , Wang Hong , Gu Wei-Min , Liang Ying-Jian , Cescon Matteo , Lv Guo-Yue , Yang Tian
Published: July 2024

e16271

Background: The role of hepatic resection in treating Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) is a subject of ongoing debate. This study aims to assess the prognostic significance of the number of nodular HCC in patients undergoing hepatic resection for intermediate-stage (BCLC stage B) HCC. Methods: An analysis was conducted using data from a multicenter database of patients who underwent curative-intent resection for BCLC intermediate-stage HCC. Patients were classified into binodular and tri(+)nodular (≥ 3 nodules) groups based on the number of tumor nodules. Long-term overall survival (OS) and recurrence-free survival (RFS) were compared between these groups. Univariate and multivariate Cox-regression analyses identified risk factors for OS and RFS. Additional comparisons were made with outcomes in patients with uninodular large HCC (single nodule > 5 cm; BCLC stage A). Results: Of the 338 patients with BCLC intermediate-stage HCC, 187 (55.3%) had binodular and 151 (44.7%) had tri(+)nodular disease. Patients with binodular HCC showed significantly better median OS (49.6 months) and RFS (22.2 months) compared to those with tri(+)nodular HCC (33.5 and 13.7 months, P = 0.036 and 0.009, respectively), and outcomes comparable to those with uninodular large HCC (59.8 and 26.8 months, P = 0.144 and 0.311, respectively). Multivariate analyses indicated that binodular HCC was independently associated with improved OS and RFS following hepatic resection in BCLC intermediate-stage HCC. Conclusions: Patients with binodular HCC exhibit more favorable survival outcomes post-resection of BCLC intermediate-stage HCC compared to those with tri(+)nodular HCC, akin to outcomes observed in BCLC early-stage uninodular large HCC. These findings highlight the prognostic relevance of nodular number in stratifying and guiding surgical decisions for intermediate-stage HCC. [Table: see text]
Genomic and biomarker analysis of immunotherapy combined with chemotherapy treated for patients with metastatic BTC cancer: A real world study.
Authors: Gou Miaomiao , Dai Guanghai , Wang Zhi-Kuan
Published: July 2024

e16373

Background: Biliary tract cancer (BTC) is a heterogeneous group of diseases with dismal prognosis. The TOPAZ-1 phase III trial and KENOTE 966 reported a survival benefit with the immune checkpoint inhibitor (ICI) plus chemotherapy (GemCis,GC) in patients with advanced BTC. Consequently, immunotherapy plus chemotherapy has become a new standard care for advanced BTC. Understanding the association between genomic alterations and immunotherapy outcomes of BTC could further improve the clinical benefits. Therefore, we conducted this real-world study in China. Methods: This study included 47 patients with metastatic BTC treated with PD-1/PD-L1(ICI) antibodies in combination with chemotherapy from January 2019 to January 2023 in Medical Oncology department of Chinese PLA General Hospital. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR). The exploration endpoint was genomic and biomarker analysis. Genomic tumor DNA was isolated from 30 patients and used for targeted next-generation sequencing genes to identify the genomic profiles. Results: 47 patients received immune checkpoint inhibitor (ICI) plus with chemotherapy in first line were enrolled in this study. The median PFS were 5.4m (95%CI,4.4-6.3), ORR and DCR was 21.3% and 83.0%, respectively. Patients were grouped into two group:AS+PD1(n=34) group and GC+ICI(n=13) group. In the AS(Albumin paclitaxel+S1)+PD1 group, mPFS was 5.0m (95%CI 3.8-6.1), ORR were 20.6% and DCR were 79.4% as we reported previously. In the GC+ ICI, mPFS was 7.9m (95%CI 4.7-11.1), ORR was 23.1% and DCR was 92.3%. There was no difference in terms of PFS, ORR and DCR between two groups. With regard to biomarker analysis, PD-L1 expression positive were 16 patients, which of mPFS were 4.2m and ORR were 18.8%, otherwise 12 patients were PDL1 expression negative, of whom mPFS were 9.1m and 33.3% as unexpected. Average TMB were 4.5mt/MB for MSS type patients. There is no difference of PFS between TMB high(>4.5mt/MB) or low(<4.5mt/MB). As for genomic analysis, the most common gene alterations were TP53(N=13, 43%))KRAS(N=8, 26.7%), NTRK1\2\3(N=8, 26.7%), IDH1/2(N=6, 20%), PIK3CA(N=6, 20%), BRCA2(N=5, 16.7%). MDM2(N=5,16.7%), BRAF(N=4,13.3%). The mutations are mainly concentrated in the DDR (20) pathway followed by the RTK-RAS (16), TP53 (13), CPF (9), FA (9), HRR (9), and PI3K (8) pathways. Compared between long term survival(PFS>5.4m)and short term survival(PFS<5.4m), MDM2 was only predictor for short survival(p<0.05). Conclusions: Compared to AS+pd-1, patients received GP+ ICI numerically had better outcomes. It seems PD-L1 and TMB were not good predictors to select patients who can more benefit from immunotherapy plus chemotherapy. MDM2 mutation suggest patients tend to less active to immunotherapy-based modality.
Predicting PAM50 subtypes from whole slide images of prostate cancer biopsies.
Authors: Nateghi Sarjezeh Ramin , Ayad Marina , Saft Madeline , Li Eric Victor , Kumar Sai , Neill Clayton , Patel Hiten D. , Schaeffer Edward M. , Liu Yang , Davicioni Elai , Yang Ximing J , Cooper Lee A.D. , Ross Ashley
Published: July 2024

e17001

Background: Computational analysis of digitized pathological images has been shown to have diagnostic and prognostic applications. Recent research suggests that molecular features, previously defined at the genomic level, might be additionally recognized. In prostate cancer, transcriptomic PAM50 molecular subtypes may correlate with patient response to systemic therapy. Here we investigate whether computational analysis of digital prostate biopsy slides can predict PAM50 category. Methods: Our study utilized digitized images of 704 prostate biopsy slides from 336 patients with prostate cancer at Northwestern Memorial Hospital with Decipher testing (Veracyte, Inc San Diego, CA). All slides analyzed contain carcinoma with the majority being primary Gleason pattern 3 (545 out of 704). Hematoxylin and eosin stained slides were scanned on a Leica GT450 scanner at 40x magnification. PAM50 subtypes were derived from the Decipher Genomic Resource Information Database (GRID). Data were split at the subject level using 80% for training, 10% for validation, and 10% for evaluation, facilitating model development and assessment. We devised a model comprising two decoupled parts: a multi-instance learning model that utilizes a multi-class attention mechanism to explore relevant class-specific information from slides, and a pre-trained network to extract high-dimensional semantic features from the tiles of WSIs. The model trained based on the WSIs of the training set to predict PAM50 subtypes (luminal A, luminal B, and basal). This attention-based training approach allowed the model to capture relevant patterns and information present in the WSIs. Following the training phase, the model was subsequently evaluated on the testing set. Results: Model AUC on the evaluation set was 0.78. Among evaluation set misclassifications, no luminal samples were misclassified as basal subtype. Conclusions: Our investigation provides preliminary results on the ability to predict RNA expression-based subtypes from prostate cancer biopsy histology. This approach may help to preserve tissue, minimize costs, and decrease turnaround time associated with molecular testing in prostate cancer while offering patients with prostate cancer opportunities for precision medicine.
Clinicopathological features and genomic profiles of prostate cancer with elevated carbohydrate antigen 19-9.
Authors: Li Yilin , Liu Yang , Yang Ping , Liu Ruiqi , Gao Jianming , An Xin , Li Yonghong , Zhou Fangjian , He Liru
Published: July 2024

e17003

Background: The elevated carbohydrate antigen 19-9 (CA199) is commonly observed in digestive system tumors, but rarely in prostate cancer (PCa). Due to the rarity and the poor understanding of the special subtype of PCa, the clinicopathological and genomic characteristics and survival outcomes in PCa patients with elevated CA199 in our center were analyzed. Methods: Cases were collected retrospectively from 2012 to 2023 in Sun Yat-sen University Cancer Center. The tumor genomic profiles were analyzed by R (http://www.rproject.org). Kaplan-Meier survival analyses were performed to compare survival outcomes. All statistical analyses were performed using SPSS version 26.0 and GraphPad Prism version 8.0. All analyses were two‐tailed, and the significance level was set at P<0.05. Results: A total of 137 PCa patients with elevated CA199 (>35ng/ml) were identified, with an exclusion of 47 patients with secondary cancers and 40 patients with other diseases that may cause elevated CA199, finally 50 cases (22 with primary and 28 with secondary elevated CA199) were included. The median initial PSA and the median time from diagnosis to CRPC were 102ng/ml and 14 months. Most patients were with a high GS score (GS≥8: 82%) and an advanced stage (M1: 84%). Poorly differentiated adenocarcinoma (22%) was frequently observed. Compared with patients with primary elevated CA199, patients with secondary elevated CA199 had higher levels of CA199 (102ng/ml vs. 78ng/ml, p=0.0456), lower levels of PSA at diagnosis (65ng/ml vs. 132ng/ml, p=0.0131) and higher proportion of poorly differentiated adenocarcinoma (36% vs. 5%, p=0.0138). The level of CA199 in patients with primary elevated CA199 was correlated with the level of CEA (R2=0.2658, p=0.0168), but not with the level of NSE or PSA. At a median follow-up of 31 months, the median OS of the whole group, primary elevated CA199 and secondary elevated CA199 subgroups was 49 months, 31 months and not reached. Secondary elevated CA199 (p=0.0009), abiraterone treatment (p<0.0001) and chemotherapy treatment (p=0.0331) were significant prognostic factors of OS. To study the genomic characteristics of PCa patients with elevated CA199, 29 PCa patients with normal CA199 were included as a control (genomic data available in 13 and 29 cases respectively). Patients with elevated CA199 were more likely to have mutations in castration resistant associated genes (AR, FOXA1, ASXL1, KMT2B, JAK2 and AKT1), malignant progression associated genes (RARA, BLM, PIK3R1) and CA199 metabolism associated gene (ERBB2). Conclusions: PCa with elevated CA199 is highly malignant and with poor prognosis. Intensive treatment with abiraterone and chemotherapy could benefit such patients. Poor pathological differentiation and the gene mutation profile may partly explain the clinical outcome.
Molecular characterization of growing teratoma syndrome in patients with testicular germ cell tumor.
Authors: Mego Michal , Horak Samuel , Hadzega Dominik , Kalavska Katarina , Kolnikova Georgina , Lesko Peter , Orszaghova Zuzana , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Aziri Ramadan , Pindak Daniel , Chovanec Michal , Kucerova Lucia , Cierna Zuzana
Published: July 2024

e17017

Background: Teratomas are unique neoplastic growths that encompass a diverse array of tissue types derived from multiple germ layers, often exhibiting varying degrees of differentiation. Among the phenomena associated with teratomas, the growing teratoma syndrome (GTS) stands out as a rare yet clinically significant occurrence. GTS, characterized by the persistence or regrowth of teratomatous elements despite initial treatment, poses challenges for both diagnosis and management. In this abstract, we present the results of our expression array analysis of teratomas, aiming to uncover novel insights into their molecular composition, heterogeneity, and potential implications for clinical management. Methods: This study included 53 patients with retroperitoneal teratoma (7 chemotherapy naïve and 46 with postchemotherapy teratoma) and 20 patients with viable postchemotherapy germ cell tumor from retroperitoneum that had surgery at National Cancer Institute in Slovakia and for whom formalin-fixed paraffin-embedded (FFPE) tumor tissue was available. Study also includes samples from 5 patients with normal testis as control group. Ten patients (18.9%) in this cohort had growing teratoma syndrome. Analysis was performed by HTG EdgeSeq Oncology Biomarker panel (HTG Molecular Diagnostics, Inc., Tucson, USA). Identified candidate genes associated with GTS were further validated by immunohistochemistry on FFPE. Results: Molecular profiling indicates no differences in expression profile in retroperitoneal teratomas regardless of previous chemotherapy. Expression analysis indicates 1586 genes being differently expressed with high significance ( p < 0.05) in teratomas compared to normal testis and 1571 genes differentially expressed compared postchemotherapy viable tumors. We identified 14 genes being differently expressed in growing teratoma syndrome compared to teratoma without growth (CYP4A22, IGFBP1, CXCL6, LTF, CYP2C8, CFTR, CCL20, PFKFB3, SLC2A3, LIPA, HMOX1, GPNMB, CCL18, DLK1. Pathway analysis revealed MAPK and PI3K−Akt signaling pathways are mostly dysregulated in GTS. Conclusions: This molecular profiling identify genes differentially expressed in teratomas that are potential biomarkers for prediction of teratoma element in postchemotherapy residues in testicular germ cell tumor patients. Moreover, inhibition of identified signaling pathways associated with GTS could represent potentially novel therapeutic targets in case of unresectable disease.