Progression-free Survival In Patients Research Articles

Radiotherapy for pediatric low-grade glioma.

Radiotherapy is a highly effective treatment for pediatric low-grade glioma, serving as the standard for evaluating progression-free and overall survival, as well as vision preservation. Despite its proven efficacy, concerns about treatment complications have led to increased use of chemotherapy and targeted therapy, which are associated with poorer progression-free survival outcomes. This review by Indu Bansal and Thomas E. Merchant examines the indications, timing, and results of radiotherapy for pediatric low-grade glioma. The authors provide a comprehensive analysis of clinical management strategies, addressing the controversies surrounding the use and timing of radiotherapy compared to other therapies. The review highlights that while radiotherapy is essential for certain patients, particularly those who are not candidates for complete resection due to the tumor's infiltrative nature or location, it is often deferred in favor of systemic therapies. This deferral can lead to significant morbidity, including poor visual outcomes. Reports indicate that systemic therapy negatively impacts progression-free survival in patients who eventually undergo radiotherapy. Newer radiotherapy techniques have been developed to minimize complications, offering potential benefits over traditional methods. The evolving clinical management of pediatric low-grade glioma involves balancing the benefits of radiotherapy with concerns about its side effects. Although systemic therapies are increasingly favored, their associated inferior progression-free survival and potential for significant morbidity underscore the need for careful consideration of radiotherapy, particularly in older children, adolescents, or those with progressive disease post-systemic therapy. The emerging role of targeted therapy presents additional challenges, including uncertainties about long-term side effects and its interaction with radiotherapy. Further research is needed to optimize treatment strategies and improve outcomes for pediatric patients with low-grade glioma.

The prognostic value of preoperative neoindices consisting of lymphocytes, neutrophils and albumin (LANR) in operable breast cancer: a retrospective study.

Preoperative inflammatory factors and nutritional status are strongly associated with the prognosis of a variety of cancers. We explored the relationship between preoperative lymphocytes, neutrophils and albumin (LANR) and progression-free survival in breast cancer patients. The clinical and follow-up data of 200 breast cancer patients were retrospectively analyzed in this study, and the value of LANR was determined as follows: LANR, lymphocytes × albumin/neutrophils. ROC curves, COX proportional risk regression analysis and subgroup analysis were used to assess the prognostic value of LANR in progression-free survival of breast cancer patients. The median age of the patients was 55.5 years (range 50-62 years). The median follow-up time was 46 months (range 33-55 months). In progression-free survival, the area under the LANR curve was 0.748 and the HR (95% CI) was 0.035 (0.679-0.817). LANR was associated with age (p=0.02), positive axillary lymph nodes (p<0.001), TNM stage (p<0.001) and human epidermal growth factor receptor 2(p=0.004). The results indicated that preoperative LANR may be a reliable predictor of progression-free survival in patients with operable breast cancer. LANR may be an essential predictor for breast cancer patients and provides a therapeutic basis for clinicians and patients.

Immune Checkpoint Inhibitor Score Predicts Survival Benefit of Immunotherapy in Patients with Non-small Cell Lung Cancer.

The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. This was a prospective multicenter study in patients with advanced nonsmall cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. A total of 143 patients from four institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p=0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p&lt;0.001). Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

Impact of diabetes on the prognosis of patients with oral and oropharyngeal cancer: A meta-analysis.

Diabetes has been related to an increased risk of oral cancer. Nevertheless, the impact of diabetes on the outcome of individuals with oral and oropharyngeal cancer is not clear. In this study, a meta-analysis was carried out to assess the link between diabetes and the survival of individuals with oral and oropharyngeal cancer. Relevant cohort studies for the meta-analysis objective were obtained through searching electronic databases, such as PubMed, Web of Science and Embase. The data were combined using a random effects model that accounted for differences between studies. A total of 10 cohorts involving 21,871 patients with oral and oropharyngeal cancer were included. Pooled results suggest that compared with those with normoglycemia, oral and oropharyngeal cancer patients with diabetes were associated with a poor overall survival (hazard ratio 1.69, 95% confidence interval 1.29-2.22, P < 0.001; I2 = 69%). Subgroup analysis suggested a stronger association between diabetes and poor overall survival in patients aged ≥52 years as compared with those aged <52 years (hazard ratio 2.08 vs 1.34, P = 0.03). Other study characteristics, such as study country, tumor stage or follow-up duration, did not seem to significantly affect the association (P for subgroup difference all >0.05). In addition, diabetes was also associated with a poor progression-free survival of patients with oral and oropharyngeal cancer (hazard ratio 1.61, 95% confidence interval 1.30-1.99, P < 0.001; I2 = 9%). Patients with oral and oropharyngeal cancer might have a poor survival if they have pre-existing diabetes.

T-antigen as a biomarker of progression-free survival in patients with glioblastoma.

Glioblastoma (GBM) is one of the most aggressive brain tumors and often leads to poor outcomes. Studies have indicated that glycan levels are significantly correlated with the pathogenesis and development of cancers. However, whether glycan levels can serve as diagnostic or prognostic biomarkers in GBM remains unclear. We obtained glycomic profiles in tissue and serum samples from 55 individuals with GBM using a well-established lectin biochip platform probing with 11 specific lectins. Our univariate analysis showed that 5 out of the 11 lectin-probed glycans (LPGs) were significantly higher in GBM tissues than in peri-tumoral tissues. After logistic regression analyses, only the Jacalin-probed T-antigen difference between the two groups remained significant (p = 0.037). Moreover, survival-related analyses showed that the level of Jacalin-probed T-antigen was significantly associated with the progression-free survival (p = 0.038) of patients. However, none of the LPG levels were correlated with the overall survival or the chemosensitivity to temozolomide therapy. The correlation coefficient analysis showed a moderate-to-strong correlation in the Jacalin-probed T-antigen levels between GBM tissues and serum samples, indicating its potential usefulness as a non-invasive GBM progression biomarker. Glycomics analyses can be helpful in the prediction of GBM recurrences and may provide information useful for GBM glycan-based target therapies or vaccine development.

Exploring the prognostic role of complex karyotype in chronic lymphocytic leukaemia patients treated with venetoclax-based regimens.

Although the unfavourable prognostic role of complex karyotype (CK) in chronic lymphocytic leukaemia (CLL) patients treated with chemoimmunotherapy has been clarified, its impact on the outcome of patients being treated with novel targeted agents, and especially with venetoclax-based regimens, remains to be resolved. In fact, only few studies, utilizing data derived from clinical trials (e.g. MURANO, CLL14, GAIA-CLL13), specifically focus on this topic while real-word evidence is missing. In our real-life retrospective study conducted on 61 patients with CLL and treated with venetoclax-based regimens in any therapeutic line, we documented a remarkable lower progression-free survival in patients harbouring both CK and high CK, while overall response rate (including complete remissions and partial remissions) and overall survival are not affected by CK in our population.

Comparing niraparib versus platinum-taxane doublet chemotherapy as neoadjuvant treatment in patients with newly diagnosed homologous recombination–deficient stage III/IV ovarian cancer: study protocol for cohort C of the open-label, phase 2, randomized controlled multicenter OPAL trial

BackgroundMaintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib’s efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination–deficient tumors.MethodsOPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator’s discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator’s discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination–deficient. The primary endpoint is the pre–interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1.DiscussionOPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination–deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery.Trial registrationClinicalTrials.gov NCT03574779. Registered on February 28, 2022.

Abstract PO3-05-05: The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors

Abstract Background: Multiple trials have proven that adding CDK4/6 inhibitors to endocrine treatment increases progression free (PFS) and overall survival (OS) of patients with metastatic estrogen receptor (ER)-positive HER2 negative breast cancer. However, only limited evidence is available of treatment efficacy of CDK4/6 inhibitors for invasive lobular carcinoma (ILC). This retrospective study aims to compare treatment duration of the three FDA/EMA approved CDK4/6 inhibitors in patients with no special type (NST) breast cancer versus patients with ILC. Methods: All patients with metastatic ER-positive HER2-negative breast cancer who were treated with a CDK4/6 inhibitor (1st, 2nd; 3rd line) in University Hospitals Leuven between December 2014 and February 2023, were included. A comparison of PFS and OS was made between patients with NST and ILC by use of the Kaplan Meier method. Other histological subtypes as well as mixed subtypes were excluded. Uni- and multivariable cox regression models were performed to quantify the association of histological subtype with PFS and OS. Results: A total of 418 patients were included of which 119 (28.5%) patients with ILC (median age at primary diagnosis 59 years, range 36 – 89 years) and 299 (71.5%) patients with NST (median age at primary diagnosis 55 years, range 23 – 90 years). Median follow-up was 26.8 months (range 1.1 – 88.1 months). Median PFS was 15.2 months (range 1.0 – 74.6 months) and 14.7 months (range 1.0 – 89.3 months) for patients with ILC and NST respectively. The OS rate after 60 months follow up was 39.2 % (CI 26.8 – 51.4) for ILC and 40.1% (CI 32.2 – 47.8) for NST. As shown in table 1, clear differences were observed in PFS rates after 12, 24 and 60 months between patients with NST that received CDK4/6 inhibitors in first line versus second or third line. These differences were less apparent for patients with ILC. For both NST and ILC, endocrine resistance at start of CDK4/6 inhibition impacted PFS rates negatively (table 2). In multivariable analyses, histological subtype was not predictive for CDK4/6 inhibition outcome (PFS: hazard ratio (HR) 0.996, CI 0.728 – 1.364, p-value 0.981; OS: HR 0.872, CI 0.602 – 1.263, p-value 0.468). Endocrine sensitivity vs. resistance at the time CDK4/6 inhibitor was started, was proven to be predictive for both PFS (HR 0.478, CI 0.337 – 0.678, p-value &amp;lt; 0.001) and OS (HR 0.528, CI 0.347 – 0.804, p-value 0.003). Conclusion: In our center, the histological subtype of breast cancer did not seem to impact PFS and OS significantly after treatment with CDK4/6 inhibition. Patients with NST seemed to have an increased benefit in PFS from treatment with CDK4/6 inhibition in first line as compared to later lines. While for patients with ILC, no difference between treatment lines were observed. Therefore, clinicians might be able to safely postpone CDK4/6 inhibitors to second- or third-line treatment in patients with metastatic ILC. Table 1: PFS rates by histological subtype and line of CDK4/6 treatment Table 2: PFS rates by histological subtype and endocrine sensitivity at start of CDK4/6 inhibition Citation Format: Cedric Bauters, Karen Van Baelen, Hans Wildiers, Giuseppe Floris, Sileny Han, Patrick Berteloot, Thaïs Baert, Ann Smeets, Ines Nevelsteen, Yannick Van Herck, Anne Deblander, Chantal Remmerie, Lieke Dullens, Maxime Van Houdt, Annouschka Laenen, Christine Desmedt, Patrick Neven. The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-05.

Abstract PO2-13-11: High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer

Abstract Background: Metastatic breast cancer can be classified into different subtypes depending on hormone receptor (HR) and HER2 status. The subtype can change during tumor progression, and repeated biopsy is needed to deliver the most appropriate treatment every time a new lesion is found. It is not always possible to get a new biopsy from metastatic sites, and therefore liquid biopsy using circulating tumor DNA (ctDNA) is suggested as an alternative method to replace conventional biopsy. Methods: We performed a prospective serial collection of 65 ctDNA samples from 17 patients with metastatic breast cancer (mBC) at Seoul National University Hospital from October 2020 to March 2022. We used IMBdx AlphaLiquid®100 method to detect the genetic changes and analyzed the correlation with clinical outcomes. Results: Median age was 45 (range 32 – 62). Fifteen patients (88.2%) were relapsed mBC and most of the patients (14/17: 82.4%) were HR-positive and HER2-negative. Most of the patients had their ctDNA examined at baseline and at the time of maximal response and/or at progression. Fifteen patients (88.2%) received systemic therapy including hormone therapy, anti-HER2 therapy, and cytotoxic chemotherapy. Eight patients (47.1%) were on the first-line treatment for mBC, and 7 patients (41.2%) were on the second or later lines for mBC at the time of baseline sampling. The concentration of ctDNA and the sum of mutated allelic frequency was calculated for each sample. The ctDNA concentration ranged from 0.71 to 1386.00 ng/mL, and the median value was 5.37 ng/mL. We dichotomized these samples into two groups, with ctDNA concentration either higher or lower than the median value. Then we analyzed progression free survival (PFS) of each group. Patients with higher ctDNA concentration showed shorter PFS (7 mo. vs. not reached, p&amp;lt; 0.001). The sum of mutated allelic frequency ranged from 0.00% to 223.46% and the median value was 6.36%. Patients with higher mutated allelic frequency showed shorter PFS (6 mo. vs. 22 mo., p&amp;lt; 0.001). In addition, the PFS was significantly worse in patients who had mutated PIK3CA (5 mo vs. 22 mo, p&amp;lt; 0.001). The patients with mutated TP53 also showed shorter PFS (6 mo vs. 17 mo, p&amp;lt; 0.001) in univariate analysis. High estrogen receptor positivity in immunohistochemistry was correlated with lower mutated allelic frequency in ctDNA (p=0.003) but had no impact on the concentration of ctDNA (p=0.165). The concentration of ctDNA differed by metastatic sites. Patients with metastases to bones (p=0.007), liver (p&amp;lt; 0.001), soft tissue or lymph nodes (p=0.002) were more likely to have higher concentrations of ctDNA, while patients with brain metastases had significantly lower ctDNA concentration (p=0.006). When the sum of mutated allelic frequency of ctDNA and metastatic sites was analyzed, bone (p=0.001), liver (p&amp;lt; 0.001), and soft tissue or lymph node (p&amp;lt; 0.001) metastases had a positive correlation, while brain had negative correlation (p=0.017). Lung or pleural metastases had no significant correlation with ctDNA, neither concentration (p=0.271) nor mutated allelic frequency (p=0.965). Conclusion: Patients with mBC with higher concentrations of ctDNA or higher mutated allelic frequency of ctDNA at baseline showed significantly shorter PFS. PIK3CAmt and TP53mt detected by liquid biopsy could be used as a poor prognostic biomarkers for mBC patients. Citation Format: Hanbaek Yi, Tae-Yong Kim, Myung Geun Song, Hwang-Phill Kim, Tae-You Kim, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-11.

Abstract PO4-16-07: Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02)

Abstract Introduction Bone marrow involvement is a rare occurrence in patients with advanced breast cancer (ABC), and the prognosis in this context is generally poor. Prompt initiation of treatment to improve the patient's hematological status is crucial. However, this condition is often excluded from clinical trials, making it challenging to determine the effectiveness of new drugs. Limited data and evidence are available to guide treatment decisions, but guidelines recommend starting with chemotherapy for the need of a rapid response. This study aims to analyze the real-world efficacy of cyclin-dependent kinase inhibitors (CDKis) in HR+/HER2- ABC with bone marrow infiltration. Methods Retrospective multicenter cohort study including HR+/HER2- ABC patients from public and private facilities in Argentina. Patients with confirmed bone marrow involvement (blood smear or histological biopsy analysis) and treated with CDKi were eligible. Bone marrow response was defined as an increase in at least one of the previously abnormal blood series to Hb &amp;gt;10.0, platelets &amp;gt;100,000, and leukocytes &amp;gt;4,000. Results A total of 22 patients from different medical centers in Argentina were included. The median age was 55.5 (IQR 46.25-65). Histological confirmation of bone marrow involvement was reported in 81.8% (18) of patients. Among them, 54.5% (12) had initial diagnosis at an early stage, and 13.6% (3) experienced relapse during or within 1 year of completing adjuvant hormonal treatment. Bone-only metastasis was observed in 50% (11) of patients, while the remaining 50% (11) had both visceral and bone disease. Anemia, thrombocytopenia, and leukopenia were present in 95.5% (21), 90.9% (20), and 40.9% (9) of patients, respectively. In 68.2% (15) of patients, bone marrow involvement was detected at the first-line treatment setting. The selected CDKis were palbociclib in 40.9% (9) of patients, ribociclib in 31.8% (7), and abemaciclib in 27.3% (6). The bone marrow response rate was 68.2% (15), with a median of 2 cycles (range 1-5) required for a response. Dose reduction was necessary in 31.8% (7) of patients. Discussion Managing patients with uncommon sites of metastasis, such as bone marrow, poses significant challenges for oncologists. Bone marrow infiltration leads to hematopoietic alterations that adversely affect the quality of life, resulting in increased risk of infections, bleeding, and other comorbidities with fatal consequences. While chemotherapy is the standard treatment in such cases, our study demonstrates that CDKis are a safe and effective option for managing these complications. Conclusion The findings of this study support the evaluation of CDKis as a standard treatment for HR+/HER2- ABC patients. Our results are in line with the recently published phase 2 clinical trial RIGHT CHOICE, which showed a prolonged progression free survival in patients treated with ribociclib and HT with HR+/HE2- ABC and visceral crisis. Citation Format: Alexis Ostinelli, Pablo Mandó, Carolina Almada, Melina Winocur, M. Agustina Ipiña, Viviana Paez, Silvia Aparicio, Sergio Rivero, Federico Waisberg, Laura Sabina Lapuchesky, Cristian Micheri, M. Belen Montenegro, Cristina Rusz Maidana, Carolina Reinhardt, Evelina Rovera, Gonzalo Gómez Abuin, Santiago Bella, Florencia Perazzo, Adrian Nervo, Andrea Aguilar, Matías Chacón, Victoria Costanzo, Valeria Caceres, Jorge Nadal. Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-07.

Abstract PO2-18-11: Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva)

Abstract Background: Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advancements in cancer treatment. Anti-programmed cell death protein 1 (Anti-PD1)/PD-L1 ICIs have improved progression-free survival in patients with metastatic triple negative breast cancer (TNBC) and pathologic complete response (pCR) and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. In addition, very interesting data show the existence of a subgroup of patients with exceptional tumour responses to monotherapy with anti-PD(L)1 ICIs. These exceptional responses are observed in various tumour types, such as colorectal or breast cancer. Although in colorectal cancer, the determinants for this extreme sensitivity to immunotherapy treatment are identified (existence of MSI) in breast cancer, this is not the case. There is still a lack of knowledge about predictive biomarkers and mechanisms of action for ICIs. Trial Design: POP-Durva (NCT05215106) is a prospective, one-arm-only study aiming at determining the pCR rate after two administrations of Durvalumab monotherapy in patients with stage I TNBC. This window-of-opportunity study will recruit 195 consecutive cases of stage I TNBC (ER &amp;lt; 1%, PR &amp;lt; 1%, HER2 negative) and TILs≥5%, eligible for short-term treatment with durvalumab. Study treatment consists of two administrations of intravenous Durvalumab monotherapy, 10mg/kg, at two weeks intervals. After study treatment, patients will receive a standard treatment strategy (surgery or neoadjuvant systemic treatment) as per physician choice. The primary endpoint is the pCR rate after treatment with Durvalumab, defined as the absence of invasive disease in the breast and negative axillary nodes (ypT0/yTis ypN0). Assessment of the primary endpoint will be performed at the surgery or at the biopsy at the end of treatment) for patients undergoing neoadjuvant treatment. For patients in whom neo-adjuvant therapy is the first standard treatment strategy (i.e. after study treatment) a breast ultrasound-guided biopsy is mandatory at the end of the treatment visit. If the biopsy-proven residual disease is demonstrated, patients can receive standard neoadjuvant therapy at the discretion of the treating investigator. Patients with biopsy-proven residual disease will be considered as having no pCR. Those with a complete response may proceed directly to surgery. The expected pCR rate with Durvalumab monotherapy is 20%. The sample size of 195 patients will allow us to estimate this expected pCR rate with a 95% confidence interval of a precision of 6.2%. Secondary objectives are objective response rate and safety. Exploratory objectives are to: a. describe immune cell dynamics associated with exceptional responses to ICI (using spectral cytometry analysis), b. describe somatic genetic contributions to the determination of immune responsiveness (using whole exome sequencing (WES) and in a subset of patient's single-cell RNA-seq), c. characterize tumour cells – immune cells' interaction/spatial distribution(using imaging mass cytometry), d. explore the association between gut microbiome composition/signatures predictive of response to ICI (using 16s rRNA sequencing) and e. identify predictive tissue/blood-based biomarkers of response and to anti-PD(L)1 ICIs therapy. A total of two dedicated FFPE samples and two fresh biopsies will be collected at the time of inclusion and at the end of treatment biopsy or on the surgical specimen. In addition, we will collect stool samples pre and at the completion of all Durvalumab treatments and blood samples at the time of inclusion, during treatment (before each Durvalumab administration) and at the end of treatment for serum and plasma extraction and whole blood to serve as a control for WES. Citation Format: Joana Mourato Ribeiro, Isabelle Pic, Quentin Blampey, Elie Rassy, Nusaibah Ibrahimi, Laura Salabert, Olivier Trédan, Monica Arnedos, Semih Dogan, Kamar Serhal Serhal, Clementine Mahaut, Alessandro Viansone, Salim Laghouati, Barbara Pistilli, Charles-Antoine Dutertre, Magali Lacroix-Triki, Jean-Yves Scoazec, Lisa Derosa, Laurence Zitvogel, Corinne Balleyguier, Nadege Bercovici, Paul-Henry Cournede, Stefan Michiels, Fabrice André. Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-11.

Abstract PO2-02-05: CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial

Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor &amp;gt;10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 &amp;lt; 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-05.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to 3 months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response at 3 months is predictive of improved overall survival and progression-free survival in patients with chronic myeloid leukemia in the chronic phase. Although about one-third of patients treated with first-line imatinib do not achieve an early molecular response, long-term overall survival and progression-free survival are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved an early molecular response after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib than those randomized to imatinib (77% vs. 44%, P<0.001). The median time to MMR was 13.9 months with dasatinib versus 19.7 months with imatinib. The safety profile was consistent with previous reports. These results demonstrate that switching to dasatinib after a suboptimal response to imatinib at 3 months leads to faster MMR, provides earlier deep molecular responses, and improves some outcomes in patients with chronic myeloid leukemia in the chronic phase.

Development and interpretation of a pathomics-driven ensemble model for predicting the response to immunotherapy in gastric cancer

BackgroundOnly a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim...

Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials.

This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Inhibitory Effects of Metformin for Pancreatic Neuroendocrine Neoplasms: Experimental Study on Mitochondrial Function

Although pancreatic neuroendocrine neoplasms (panNENs) are much less common and have a better prognosis than exocrine pancreatic cancers, their recurrence rate is not low, even in Grade 1 (World Health Organization classification) panNEN. Recently, there have been several reports that the progression-free survival in patients with unresectable panNEN could be improved by an antidiabetic drug, metformin, with the co-treatment of everolimus or a somatostatin analog. In this study, we aimed to evaluate the effects of metformin on cell metabolism and viability using the panNEN cell line, QGP-1, and RIN-m in culture. We observed an inhibitory effect of metformin on QGP-1 cell proliferation in a dose-dependent manner. Metformin was found to decrease the oxygen consumption rate in QGP-1 and RIN-m cells after metformin 48 h treatment and immediately after exposure. Cell proliferation was suppressed after metformin treatment. Phosphorylated adenosine monophosphate-activated protein kinase (AMPK) expression was increased, and cyclin D1 expression was decreased in RIN-m cells 24 h after metformin treatment by Western blotting in a dose-dependent manner. In conclusion, suppressive mitochondrial respiration and AMPK activation by metformin are, thus, suggested to inhibit panNEN cell viability and cell survival.

Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells.

Glioblastoma multiforme (GBM)-induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex. The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR). Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex. Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

The safety and use of perioperative dexamethasone in the perioperative management of primary sporadic supratentorial meningiomas.

Despite the lack of prospective evidence for the perioperative use of dexamethasone in meningioma surgery, its use is well established in the daily routine of several centers. The present study evaluates the effect of dexamethasone on postoperative complications, peritumoral T2/FLAIR hyperintensity, and progression-free survival in patients with supratentorial meningiomas undergoing resection. A total of 148 patients who underwent resection of a primary sporadic supratentorial meningioma at the authors' institution between 2018 and 2020 were included in this retrospective cohort. Safety criteria were side effects of dexamethasone (e.g. hyperglycemia), surgical morbidities, length of stay, and mortality. The individual Karnofsky Performance Scales (KPS) were evaluated regarding the individual development and the delta of KPS at 3- and 12-months compared to baseline KPS was calculated. Longitudinal assessment of the peritumoral T2-/FLAIR hyperintensity changes was performed. The use of both pre- and postoperative dexamethasone did not influence the incidence rates of wound infections, infarctions, postoperative seizures, pulmonary embolism, postoperative hemorrhage, mortality, length of stay, new-onset hyperglycemia and new neurological deficits. Perioperative Dexamethasone use was associated with an improved Karnofsky performance development at 3- (delta of KPS 3.3 vs. -1.9, p=0.001) and 12-months (delta of KPS 3.8 vs. -1.1, p=0.008) compared to the preoperative Karnofsky performance status. Multivariable analysis revealed that perioperative dexamethasone use enhances the KPS improvement (OR: 3.65, 95% CI: 1.01-13.18, p=0.048). Persistent peritumoral T2/FLAIR hyperintensity changes were observed in 35 cases of 70 patients with available follow-up images and a baseline edema (50.0%). Perioperative dexamethasone use enhanced the reduction of the preoperative peritumoral T2-/FLAIR hyperintensity changes (mean reduction of maximum diameter: 1.8 cm vs. 1.1 cm, p=0.023). Perioperative dexamethasone use was independently associated with a lower risk for persistent peritumoral T2-/FLAIR hyperintensity changes (OR: 3.77, 95% CI: 1.05-13.54, p=0.042) The perioperative use of dexamethasone did not influence the progression-free survival time in Simpson grade I or II resected WHO grade 1 meningiomas (log-rank test: p=0.27). Perioperative dexamethasone use seems to be safe in surgery for primary supratentorial meningiomas. Dexamethasone use might enhance the functionality by reducing postoperative peritumoral T2-/FLAIR hyperintensities. These findings highlight the need for prospective data.

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.