Conventional Cytotoxic Chemotherapy Research Articles

Real-world incidence of incident noninfectious uveitis in patients treated with BRAF inhibitors: a nationwide clinical cohort study

To compare the incidence of noninfectious uveitis in skin melanoma or lung cancer patients who received BRAF inhibitors with that in those who received immune checkpoint inhibitors (ICIs) or conventional cytotoxic chemotherapy. Nationwide population-based retrospective clinical cohort study METHODS: From the Health Insurance Review and Assessment Service database of South Korea, we retrospectively defined 77,323 patients with skin melanoma or lung cancer who received BRAF inhibitor therapy (BRAF inhibitor-exposed group; n = 396), ICIs (ICI-exposed group; n = 22,474), or conventional cytotoxic chemotherapy (unexposed group; n = 54,453). We calculated the 1-year cumulative incidence of noninfectious uveitis in each group from the first day of BRAF inhibitor, ICI, or cytotoxic agent administration. During the first year of treatment initiation, the cumulative incidence of uveitis was 0.33%, 0.35%, and 2.27% in the unexposed, ICI-exposed, and BRAF inhibitor-exposed groups, respectively. Adjusted hazard ratios (aHR) indicated a 7.52-fold and 5.68-fold increased risk of uveitis in the BRAF inhibitor-exposed group compared with that in the unexposed and ICI-exposed groups (95% confidence interval [CI] 3.83-14.75, P < 0.001 and 95% CI 2.81-11.47, P < 0.001, respectively). After 1:4 propensity score matching, aHRs showed a 35.51-fold and 15.80-fold increased risk (95% CI 4.49-280.48, P = 0.001 and 95% CI 1.76-141.00, P = 0.014) of uveitis and severe uveitis, respectively, in the BRAF inhibitor-exposed versus unexposed patients. Crossover analysis within the BRAF inhibitor-exposed group showed a 3.71-fold increase in uveitis risk during 1-year post index date in comparison with 1-year prior to index date (95% CI 1.03-13.40, P = 0.046). In the BRAF inhibitor-exposed group, female sex, chronic kidney disease, and melanoma were associated with a trend of increased, albeit nonsignificant, risk of uveitis. Melanoma or lung cancer patients treated with BRAF inhibitors showed significantly higher risk of noninfectious uveitis than patients treated with conventional cytotoxic drugs or ICIs. These findings emphasize the importance of pretreatment patient education on BRAF-inhibitor-associated uveitis risk to enable prompt ophthalmic evaluation and treatment if symptoms arise during drug administration.

Serum Stabilin1 as a Prognostic Marker in Adults Acute Leukemia Patients

Abstract Background STAB-1 (common lymphatic endothelial and vascular endothelial receptor) was found to be expressed on tumor lymphatic vessels in different malignancies and it is a bad prognostic marker. This study will assess the role of serum stabilin1 (STAB1) as a prognostic marker in adult patients with newly diagnosed acute leukemia and correlate it with the other well established prognostic markers. Acute lymphoblastic leukemia (ALL) is a hematologic malignancy arising from precursors of the lymphoid lineage. Conventional cytotoxic chemotherapies have resulted in high cure rates of up to 90% in pediatric ALL, but the outcomes for adult patients remain suboptimal with 5-year survival rates of only 30%-40%. Aim of the Work To measure STAB1 expression in patients with AML and patients with ALL and assess its role as a prognostic factor with correlating it with other prognostic factors. Patients and Methods A case control study in Ain Shams University Hospitals, Clinical Haematology and Oncolgy division of Internal Medicine Department for one year on total 75 subjects divided into: 25 patients with newly diagnosed acute myeloid leukemia (AML), 25 patients with newly diagnosed acute lymphoblastic leukemia (ALL) and 25 age and sex matched healthy control subjects. The study population was recruited from Ain Shams University Hospitals, Clinical Haematology and Oncolgy division of Internal Medicine Department. Results There was no significant difference between cases of acute leukemia pts and control group as there was no statistically significant difference between control and patients group regarding sex, age, spleen size, liver size, LDH, CRP, uric acid and ESR of the studied subjects. Our study shows that as regard CBC; there was significant difference between the studied groups as regard leucocytic count, BUT Platelets, and hemoglobin was insignificant, which was also described in the study. Our study showed that there was high statistically significant difference between the acute leukemia patients and the healthy control group as regard sabilin1. Our study shows that the mean serum level of stabilin1 in the patients who didn’t respond to chemotherapy was higher than that of the patients that responded to chemotherapy. Conclusion There was high statistically significant difference between the studied groups as stabilin1. There was significant correlation between stabilin2 and chemotherapy response. Stabilin1 expression levels also identified a new subgroup at a higher risk for relapse and with a poor prognosis in acute leukemia patients. Stabilin 1 can be used as a prognostic factor in patients with acute leukemia.

Cancer drugs and acute kidney injury: new therapies and new challenges.

Cancer therapies continue to evolve at a rapid pace and although novel treatments, including immunotherapies and targeted therapies have allowed for substantial improvements in cancer survival, they carry associated risks of acute kidney injury (AKI). We aim to summarize the existing literature on AKI associated with the spectrum of systemic cancer treatments, including conventional chemotherapies, newer immunotherapies, and the growing number of targeted cancer therapies, which may be associated with both AKI and 'pseudo-AKI'. Conventional cytotoxic chemotherapies (e.g. cisplatin and other platinum-based agents, methotrexate, pemetrexed, ifosfamide, etc.) with well recognized nephrotoxicities (predominantly tubulointerstitial injury) remain in widespread use. Immunotherapies (e.g., immune checkpoint inhibitors and CAR-T therapies) may be associated with kidney immune-related adverse events, most often acute interstitial nephritis, and rarely, glomerular disease. Recently, multiple targeted cancer therapies have been associated with reduced renal tubular secretion of creatinine, causing elevations in serum creatinine and apparent 'pseudo-AKI'. To complicate matters further, these agents have had biopsy-proven, 'true' kidney injury attributed to them in numerous case reports. Clinicians in nephrology and oncology must be aware of the various potential kidney risks with these agents and recognize those with clinically meaningful impact on both cancer and kidney outcomes.

Low-grade glioma in children with neurofibromatosis type 1: surveillance, treatment indications, management, and future directions.

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome characterized by the development of both central and peripheral nervous system tumors. Low-grade glioma (LGG) is the most prevalent central nervous system tumor occurring in children with NF1, arising most frequently within the optic pathway, followed by the brainstem. Historically, treatment of NF1-LGG has been limited to conventional cytotoxic chemotherapy and surgery. Despite treatment with chemotherapy, a subset of children with NF1-LGG fail initial therapy, have a continued decline in function, or recur. The recent development of several preclinical models has allowed for the identification of novel, molecularly targeted therapies. At present, exploration of these novel precision-based therapies is ongoing in the preclinical setting and through larger, collaborative clinical trials. Herein, we review the approach to surveillance and management of NF1-LGG in children and discuss upcoming novel therapies and treatment protocols.

Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates.

Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

Abstract 533: Attenuating EZH2-mediated metastasis and tumor growth by pharmacological-based approaches using three-dimensional in vitro culture models

Abstract Triple Negative breast cancer (TNBC) accounts for 10-15% of all breast cancers where patients encounter poor clinical outcomes. Treatment modalities for TNBC are conventional cytotoxic chemotherapy and radiation leads to 35%-40% relapse within 5 years of diagnosis. There is a growing need for more effective targeted therapeutics to inhibit TNBC growth. The role of EZH2 in maintaining tumor growth and metastasis in TNBC is well documented. EZH2 promotes breast tumor-initiating cell expansion (BITC) and cancer progression by impairing the DNA damage repair process favoring activation of oncogenes. Despite the advancement in the discovery of inhibitors for EZH2 that attenuate its catalytic activity, resistance to these small molecules limits their use in solid tumors. The neurotransmitter dopamine via its D1 receptor activation in TNBC cell lines induces apoptosis and autophagy, as well as inhibits the invasion and regress in mammary tumors in vivo. Here we hypothesize that the presence of dopamine D1 receptor agonist (A77636) enhances the efficacy of EZH2 inhibitors (GSK126) to inhibit in vitro TNBC tumor growth and metastasis. To test the efficacy of the combination we employed a 3D culture system of MDA-MB-231 cells encapsulated in calcium-alginate microgels seeded from a microfluidic droplet generator. We also employed a 3D organ-on-chip-based microphysiological (MPS) platform (SynTumor) to study the effect of the drug combination on metastasis in vitro. The SynTumor MPS devices replicate the pathophysiological architecture of native vascularized breast tumors. The combination treatment enhanced a significant reduction of tumor spheroid diameter compared to the vehicle and indicated spheroid regression over treatment. Furthermore, the combination therapy induced necrosis and caused complete inhibition of EZH2 expression. The knockdown of EZH2 inhibited tumor spheroid formation and displayed cytoskeleton de-arrangement. In the microfluidic SynTumor model, circulating tumor cell numbers were reduced by half at 96 hrs after EZH2 combination treatment. Our data indicate that the combinatorial effect of DRD1 agonist and EZH2 inhibitor efficiently attenuates the EZH2-mediated in vitro tumor growth and metastasis (This work is supported by DOD: W81XWH2010065, for Eswar Shankar). Citation Format: xilal Rima, Gautam Sarathy, Chunyu Hu, Divya S. Patel, Deborah Ramsey, Lara Rizotto, Dario Palmeri, Gwen Fewell, Bhuvaneswari Ramaswamy, Eduardo Reátegu, Eswar Shankar. Attenuating EZH2-mediated metastasis and tumor growth by pharmacological-based approaches using three-dimensional in vitro culture models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 533.

Abstract 3327: L-pampo™, a TLR2/3 agonist, enhances anti-tumor immune responses and synergistically improves the anti-tumor efficacy of immune checkpoint inhibitors in cold tumors

Abstract Introduction: Immunotherapy is a promising therapeutic approach for a wide range of cancers. However, some tumors called "cold tumors" lack infiltrating T-cells and are not responsive to immune checkpoint inhibitors (ICIs), leading to worse clinical outcomes. This study demonstrates that L-pampo, a novel TLR2/3 agonist, promotes an anti-tumor immune response in cold tumors. Also, combining L-pampo with ICIs can improve the anti-tumor efficacy more safely than standard-of-care (SoC) chemotherapies. Method: We utilized syngeneic tumor models using CT26 colon cancer and 4T1 triple-negative breast cancer (TNBC). L-pampo was administered alone or in combination with ICIs such as anti-PD-1 (aPD-1) and anti-CTLA-4 (aCTLA-4) antibodies to tumor-bearing mice (n=8/group). Tumor size was measured every three days, and the survival rate was monitored until day 60. On day 21 or 27 after transplantation, we analyzed the tumor weight and tumor-infiltrating immune cells. Furthermore, we assessed the respective anti-tumor efficacies and safety of L-pampo and SoC chemotherapies (FOLFOX and paclitaxel). Result: In the CT26 colon cancer model, L-pampo effectively reduced the tumor size compared to the vehicle group (83.7%). The combination of L-pampo and ICI reduced tumor size by 86.1% (with aCTLA4) and 90.5% (with aPD-1), while the ICI alone did not effectively inhibit tumor growth (aPD-1; 17.3%, aCTLA-4; 23.6%). Notably, the triple concurrent treatment with L-pampo, aPD-1 and aCTLA-4 reduced tumor size by 96.6% and induced completed tumor regression in 1 out of 8. In the 4T1 TNBC model, L-pampo reduced tumor size by 64.2% compared to the vehicle treatment, and combined treatment with L-pampo and a-PD-1 suppressed tumor growth compared to aPD-1 alone (9.6% vs. 61.5%). Additionally, L-pampo improved median overall survival in each tumor model (CT26; 25.5 vs. 35.5, 4T1; 29.5 vs. 53.5 days). To compare the anti-tumor efficacy of L-pampo and conventional cytotoxic chemotherapy, we treated tumor-bearing mice with FOLFOX or paclitaxel as SoC regimen, respectively. Compared with each chemotherapy, L-pampo revealed comparable antitumor efficacies (Tumor growth inhibition CT26; 75.6% vs. 70.6%, 4T1; 65.5% vs. 58.8%). Interestingly, L-pampo inhibited tumor growth without significant adverse effects. In contrast, conventional chemotherapies induced acute hematological side effects such as leukopenia/neutropenia/thrombocytopenia and rapid weight loss. Furthermore, L-pampo increased the active cytotoxic T-cells infiltration through antigen-presenting cells stimulation within the tumors. Conclusion: This study suggests that L-pampo, a novel TLR2/3 agonist, can be a potent anti-tumor agent, improving the anti-tumor efficacy of ICIs in cold tumors with enhanced anti-tumor immunity and minimal toxicities than conventional chemotherapies. Citation Format: Guentae Kim, Yoonki Heo, Hye Jung Kim, Sejung Park, Byung Cheol Ahn, Won Suk Lee, Chan Kim, Hong Jae Chon, Eunyoung Chun, Jung Sun Yum. L-pampo™, a TLR2/3 agonist, enhances anti-tumor immune responses and synergistically improves the anti-tumor efficacy of immune checkpoint inhibitors in cold tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3327.

Tumor-Stroma Proportion to Predict Chemoresistance in Patients With Ovarian Cancer

Platinum-based chemotherapy is the backbone of standard-of-care treatment for patients with advanced-stage, high-grade serous carcinoma (HGSC), the most common form of ovarian cancer; however, one-third of patients have or acquire chemoresistance toward platinum-based therapies. To demonstrate the utility of tumor-stroma proportion (TSP) as a predictive biomarker of chemoresistance of HGSC, progression-free survival (PFS), and overall survival (OS). This prognostic study leveraged tumors from patients with HGSC in The Cancer Genome Atlas (TCGA) cohort (1993-2013) and an independent cohort of resected clinical specimens from patients with HGSC (2004-2014) available in diagnostic and tissue microarray formats from the University of Tübingen in Germany. Data analysis was conducted from January 2021 to January 2024. Diagnosis of HGSC. Principal outcome measures were the ability of TSP to predict platinum chemoresistance, PFS, and OS. Using hematoxylin and eosin-stained slides from the Tübingen cohort (used for routine diagnostic assessment from surgical specimens) as well as tissue microarrays, representative sections of tumors for scoring of TSP were identified using previously evaluated cutoffs of 50% stroma or greater (high TSP) and less than 50% stroma (low TSP). Digitized slides from the TCGA Cohort were analyzed and scored in a similar fashion. Kaplan-Meier time-to-event functions were fit to estimate PFS and OS. The study included 103 patients (mean [SD] age, 61.6 [11.1] years) from the TCGA cohort and 192 patients (mean [SD] age at diagnosis, 63.7 [11.1] years) from the Tübingen cohort. In the TCGA cohort, there was no significant association of TSP levels with chemoresistance, PFS, or OS. However, in the Tübingen cohort, high TSP was associated with significantly shorter PFS (HR, 1.586; 95% CI, 1.093-2.302; P = .02) and OS (hazard ratio [HR], 1.867; 1.249-2.789; P = .002). Patients with chemoresistant tumors were twice as likely to have high TSP as compared to patients with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; P = .01). In tissue microarrays from 185 patients from the Tübingen cohort, high TSP was again associated with significantly shorter PFS (HR, 1.675; 95% CI, 1.012-2.772 P = .04) and OS (HR, 2.491; 95% CI, 1.585-3.912; P < .001). In this prognostic study, TSP was a consistent and reproducible marker of clinical outcome measures of HGSC, including PFS, OS, and platinum chemoresistance. Accurate and cost-effective predictive biomarkers of platinum chemotherapy resistance are needed to identify patients most likely to benefit from standard treatments, and TSP can easily be implemented and integrated into prospective clinical trial design and adapted to identify patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment at the time of initial diagnosis.

Allogeneic Stem Cell Transplant and CD30 Directed CART Cell Therapies Are Associated with Improved Survival in Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers

Background: Patients (pts) with classical Hodgkin Lymphoma (cHL) who become refractory to both BV and anti-PD-1 therapies (double refractory, DR) or intolerant (INT) of BV and anti-PD-1 therapies have limited treatment options. There is limited information regarding optimal treatment approaches in these pts. Rechallenging with BV or anti-PD-1 therapies has been previously described in small cohorts with variable success. Allogeneic stem cell transplantation (alloSCT) remains the only curative approach in multiply relapsed/refractory cHL. This study aims to assess practice patterns and outcomes in a large cohort of pts with DR or INT cHL. Methods: We conducted a retrospective study of adult pts with cHL from 14 U.S. academic medical centers who developed DR or INT cHL between Jan 2011 and Dec 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) while on therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as having toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The co-primary endpoints were progression free survival (PFS) and overall survival (OS) in pts with DR/INT cHL. Time-to-event analyses were evaluated by Kaplan-Meier methods and log-rank tests. Results: A total of158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (yrs, range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage 4, and 60% primary refractory. DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT. The median OS from the time of DR/INT was 7.4 yrs (95%CI 4.1-NR). There was no difference in OS by DR and INT pts (log-rank p=0.33). The majority (87%, n=137) received subsequent lines of therapy after DR/INT (median 2, range 0-14). Next line of therapy after DR/INT was BV or anti-PD-1 rechallenge (with or without combination therapy) in 39 pts (29%), conventional cytotoxic chemotherapy in 62 pts (45%), immunomodulatory based therapy (lenalidomide, everolimus) in 16 pts (12%) or other in 20 pts (15%). Any line of therapy after DR/INT included alloSCT in 29 pts (18%) and CD30 directed chimeric antigen receptor T-cell (CART) therapy in 24 pts (15%). Forty pts (25%) were rechallenged with BV based therapies. The majority (88%) were previously refractory to BV. The median time from DR/INT to BV rechallenge was 348 days (range 14-1186). The objective response rate (ORR) was 63%, complete response rate (CRR) was 33%, and median PFS was 183 days (95%CI 108-273). Fifty-nine pts (37%) were rechallenged with anti-PD-1 based therapies. The majority (88%) were previously refractory to anti-PD-1 therapy. The median time from DR/INT to anti-PD-1 rechallenge was 233 days (range 3-1409). The ORR was 54%, CRR was 27%, and median PFS was 182 days (95%CI 127-357). There was no difference in PFS comparing BV and anti-PD-1 rechallenge (p=0.50) and no OS benefit of either BV or anti-PD-1 rechallenge, p=0.19 and 0.80 respectively. In 29 pts treated with alloSCT, the median time from DR/INT to alloSCT was 220 days (range 27-1971). AlloSCT was associated with longer OS compared to pts not treated with alloSCT (p&amp;lt;0.001), Figure 1. 3-year OS estimate was 96% (95%CI 75-99%) with alloSCT and 56% (95%CI 46-65%) without alloSCT. In 24 pts treated with CD30 directed CART, the median time from DR/INT to CART was 255 days (range 76-1600). CD30 directed CART was associated with longer OS compared to pts not treated with CART (p=0.009), Figure 2. 3-year OS estimate was 86% (95%CI 62-95%) with CART and 60% (95%CI 50-69%) without CAR-T. Only 2 pts were treated with both alloSCT and CART after DR/INT indicating that OS benefit was independent of cross over treatment. Conclusion: To our knowledge, this is the largest cohort analyzing treatment outcomes in pts refractory to, or intolerant of BV and anti-PD-1 therapy. Additionally, this study represents one of the largest evaluations of BV or anti-PD-1 rechallenge after prior DR or INT. BV and anti-PD-1 rechallenge were effective with high ORR, but median PFS with rechallenge was less than a year, indicating that rechallenge could be considered as a therapeutic bridge. There was no OS benefit of BV or anti-PD-1 rechallenge. AlloSCT and CD30 directed CART were highly effective and associated with longer OS. Pts with DR/INT cHL should be considered for alloSCT or CD30 directed CART.

BAX Mutated Clonal Hematopoiesis Arises Following Treatment with the BCL2 Inhibitor Class of Therapeutics across a Range of Hematological and Non-Hematological Neoplasms

Clonal hematopoiesis (CH) is an age-related phenomenon characterized by the expansion of genomically mutated hematopoietic clones with a selective fitness advantage. Venetoclax, a selective BCL2 inhibitor, has established efficacy in hematological malignancies such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Our previous studies described the emergence of deleterious BAX variants within the myeloid compartment of patients (pts) receiving venetoclax for CLL (Blombery, Blood2022). Whether this phenomenon is specific to venetoclax and the CLL disease context is currently unknown. We therefore aimed to investigate the prevalence and pattern of BAX-mutatedCH across different hematological and non-hematological neoplasms in response to BCL2 inhibitor therapy (both venetoclax and BGB-11417). We first examined pts with AML in complete morphologic remission after venetoclax exposure in both the newly diagnosed (CAVEAT; Chua, JCO 2020) and early relapse (VALDAC; Tiong, ASH 2022) settings using unique molecular index-based error-corrected next generation sequencing with a sensitivity of 0.5% (QIAseq targeted DNA panel). BAX variants were detected in remission samples in 11/20 (55%) and 9/26 (35%) pts in these cohorts, respectively, after a median of 9- and 4-months post venetoclax. This represented a significant higher incidence compared to remission samples from pts with newly diagnosed AML post conventional cytotoxic chemotherapy without venetoclax (6/87 [7%]; adjusted p&amp;lt;0.01 for both pairwise comparisons). Having observed the increased frequency of BAX-mutated CH in remission in myeloid (AML) and lymphoid (CLL) neoplasms, we then investigated whether BAX variants may be acquired in response to BCL2 inhibitor therapy outside the context of hematological neoplasm. We assessed a cohort of pts with metastatic breast cancer who received venetoclax in combination with tamoxifen (mBEP; Lok, Cancer Discover 2019), and detected BAX variants from peripheral blood samples in 5/16 (31%) pts (median age 66) after a median duration of 20 (range 13-44) months on venetoclax. In contrast, no BAX variants were detected in a similarly aged control cohort of 50 pts (median age 62) with breast cancer without exposure to venetoclax (p=0.01). The rates of any CH-related mutation were 75% and 50% pts, respectively (p=0.09). No pt developed MDS or AML during follow up in the mBEP cohort. Finally, to explore whether emergence of BAX-mutated CH is specific to venetoclax as an agent, we studied a cohort of 9 pts with CLL who had received BGB-11417, a more potent and selective BCL2 inhibitor; median treatment duration 13 months. Notably, we observed the emergence of BAX variants in 2/9 (22%) pts in this cohort. The characteristics of the BAX variants (n=88) in 28 pts (AML, CLL or breast cancer) are summarized in Figure 1; 3 variants (in 3 pts) were detectable in pre-treatment samples. Over half of the missense (n=22) or in-frame variants (n=1) were clustered in the C-terminus of the BAX protein, while truncating variants (n=65) were observed throughout the gene. The median number of BAX variants per pt was 2, with 32% of pts having ≥3 variants (max=13). The median VAF was 1.4%, and only 16% of variants had a VAF &amp;gt;5%. The number and VAF of BAX variants did not significantly correlate with the duration of therapy. Among 12 pts with AML who had serial testing (median inter-test interval 10 months), BAX variants (n=24) did not significantly change in VAF (median Δ 0.7%) with time after initial acquisition (Pearson's coefficient 0.17). To clarify the compartments affected by BAX variants we performed single-cell combined DNA/protein sequencing (Tapestri) of a sample with multiple BAX variants and demonstrated their presence in multiple independent clones with myeloid-biased lineage but also within the natural killer cell compartment ( Figure 2). In summary, the emergence of BAX-mutated CH appears to be a generalized phenomenon of adaptive hematopoiesis that occurs across both hematological and non-hematological malignancy settings as well being observed with other BCL2 inhibitors consistent with a therapeutic class effect. Further research is needed to understand the contribution of this phenomenon to the subsequent development of clinically relevant hematological abnormalities and its implications for future therapeutic resistance.

Cemiplimab as First Line Therapy in Advanced Penile Squamous Cell Carcinoma: A Real-World Experience.

In the treatment of cancer, immune checkpoint inhibitors (ICIs) have demonstrated significantly greater effectiveness compared to conventional cytotoxic or platinum-based chemotherapies. To assess the efficacy of ICI's in penile squamous cell carcinoma (pSCC) we performed a retrospective observational study. We reviewed electronic medical records of patients with penile squamous cell carcinoma (SCC), diagnosed between January 2020 and February 2023. Nine patients were screened, of whom three were ineligible for chemotherapy and received immunotherapy, cemiplimab, in a first-line setting. Each of the three immunotherapy-treated patients achieved almost a complete response (CR) after only a few cycles of therapy. The first patient had cerebral arteritis during treatment and received a high-dose steroid treatment with resolution of the symptoms of arteritis. After tapering down the steroids dose, the patient continued cemiplimab without further toxicity. The other two patients did not have any toxic side effects of the treatment. To the best of our knowledge, this is the first real world report of near CR with cemiplimab as a first-line treatment in penile SCC.

Efficacy of Chemotherapy After Immune Checkpoint Inhibitor Discontinuation in Head and Neck Cancer.

Immune checkpoint inhibitors (ICI) have become widely used becuse of their effectiveness and relatively low rate of severe adverse events. However, active treatment should be continued after discontinuation of ICI as response rates are lower than that of conventional cytotoxic chemotherapy. The purpose of the present study was to determine the efficacy of treatment after ICI discontinuation. This was a retrospective study from hospital charts of 99 consecutive cases treated with ICI at our facility since 2017. Of these, 79 cases of squamous cell carcinoma which had already discontinued ICI were enrolled in the present study. After discontinuation of ICI, 40 cases received active treatment with salvage chemotherapy (SCTx; 33 cases) or surgery or radiotherapy (seven patients) and 39 cases received nonactive treatment. SCTx comprising paclitaxel and cetuximab (PTX-Cmab) was administered to 15 cases and other SCTx regimens to 18 cases. A significant increase in overall survival (OS) was observed with active treatment compared with nonactive treatment. No significant differences in OS or progression-free survival (PFS) were observed between SCTx regimens; however, there was a trend toward increased survival with PTX-Cmab. Univariate analysis of overall response rate (ORR) demonstrated significant differences in the site of disease at ICI and SCTx regimens. A significant difference in disease control rate was observed between SCTx regimens. Multivariate analysis of ORR demonstrated a significant correlation with PTX-Cmab treatment. Active treatment after ICI discontinuation and the use of PTX-Cmab as SCTx may increase OS in head and neck squamous cell carcinoma. 4 Laryngoscope, 134:228-235, 2024.

Clinical outcomes of extramammary Paget’s disease in Korea: A multicenter, retrospective study.

e21599 Background: Extramammary Paget’s disease (EMPD) is very rare disease. Due to its rarity, there have been few clinical trials and no standard therapy to date. In this multicenter retrospective study, we investigated the treatment patterns and outcomes of Korean patients with advanced/metastatic extramammary Paget’s disease. Methods: As a retrospective multicenter study, we searched the medical record from 15 centers participating Rare Cancer Committee in Korean Cancer Study Group (KCSG). Results: A total of 54 patients were identified, and 11 patients who refused or did not receive treatments were excluded. In remaining 43 patients, 9 patients received locoregional therapy as first-line treatment and 34 patients initially received systemic chemotherapy. In 34 patients who received systemic chemotherapy as first-line treatment, cisplatin plus 5-fluorouracil was the most frequently used chemotherapy regimen (n = 19). Cisplatin plus 5-fluorouracil regimen achieved an objective response rate of 42.1% and a median PFS of 7.9 months. The next frequently used chemotherapy regimen was docetaxel monotherapy (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 8.5 months. There was no statistical difference between the two treatments (p = 0.29). Two patients received trastuzumab plus paclitaxel regimen as first-line therapy. Both obtained partial response, with PFS of 13.0+ and 8.2+ months respectively. Seventeen patients received second-line chemotherapy for disease progression. In 17 patients who received systemic chemotherapy as second-line treatment, docetaxel monotherapy was the most frequently used chemotherapy regimen (n = 6). Docetaxel monotherapy achieved an objective response rate of 50.0% and a median PFS of 4.5 months. Two patients received trastuzumab plus paclitaxel regimen as second-line therapy. Both obtained partial response, with PFS of 8.7 and 12.7 months respectively. In 4 patients received trastuzumab plus paclitaxel during first- and second-line chemotherapy, trastuzumab plus paclitaxel achieved an objective response rate of 100% and a median PFS of 10.7+ months. Overall, most patients with advanced/metastatic extramammary Paget’s disease could receive up to median two lines of chemotherapy and obtained median overall survival of 20.8 months. Conclusions: Due to its rarity, advanced or metastatic EMPD still has no established standard treatment. Results of our study indicate that there is no significant difference between cisplatin plus 5-fluorouracil and docetaxel treatment in the first-line treatment. The combination of trastuzumab with paclitaxel has longer survival than conventional cytotoxic chemotherapy only.

Clinical uses and safety concerns of tyrosine kinase inhibitors with a focus on novel drugs: A narrative review.

Objective:To review the safety issues surrounding tyrosine kinase inhibitors (TKIs), specifically, hematological adverse effects, cardiovascular issues, renal adverse effects and nephrotoxicity, endocrine system adverse effects, concerns related to the reproductive system, dermatological and gastrointestinal adverse effects. Data Sources: A literature search was performed through Web of Science, PubMed, Google Scholar, Scopus, and the Food and Drug Administration. Data Summary: Several safety issues have been raised following the use of TKIs. Most TKIs show hematological side effects. Considering cardiovascular toxicities, as opposed to imatinib which is relatively safe, new-generation TKIs may be associated with severe cardiovascular side effects. Both acute and chronic renal failure were reported with TKIs such as gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. Many endocrine adverse effects have been reported including hypercholesterolemia and hypertriglyceridemia (with lorlatinib) and thyroid dysfunction (with dasatinib). TKIs may interfere with fetus implantation, growth, and gonadal development. Females receiving TKIs and encountering unwanted pregnancy may have a normal pregnancy, miscarriage, or an abnormality in the fetus. Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI. Gastrointestinal side effects are common with TKIs. Diarrhea was the most frequently reported adverse effect of many TKIs. Conclusions: TKIs are increasingly taking up a critical role in the treatment of cancers due to their specific action toward malignant cells compared to conventional cytotoxic chemotherapy. Despite a dramatic improvement in the survival of patients with cancer following approval of TKIs, various early and late adverse effects were reported.

A perspective of immunotherapy for acute myeloid leukemia: Current advances and challenges.

During the last decade, the underlying pathogenic mechanisms of acute myeloid leukemia (AML) have been the subject of extensive study which has considerably increased our understanding of the disease. However, both resistance to chemotherapy and disease relapse remain the principal obstacles to successful treatment. Because of acute and chronic undesirable effects frequently associated with conventional cytotoxic chemotherapy, consolidation chemotherapy is not feasible, especially for elderly patients, which has attracted a growing body of research to attempt to tackle this problem. Immunotherapies for acute myeloid leukemia, including immune checkpoint inhibitors, monoclonal antibodies, dendritic cell (DC) vaccines, together with T-cell therapy based on engineered antigen receptor have been developed recently. Our review presents the recent progress in immunotherapy for the treatment of AML and discusses effective therapies that have the most potential and major challenges.

Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective.

Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.

Dancing with the Surgeon: Neoadjuvant and Adjuvant Immunotherapies from the Medical Oncologist's Perspective.

Perioperative treatment with conventional cytotoxic chemotherapy for resectable non-small cell lung cancer (NSCLC) has proven clinical benefits in terms of achieving a higher overall survival (OS) rate. With its success in the palliative treatment of NSCLC, immune checkpoint blockade (ICB) has now become an essential component of treatment, even as neoadjuvant or adjuvant therapy in patients with operable NSCLC. Both pre- and post-surgery ICB applications have proven clinical efficacy in preventing disease recurrence. In addition, neoadjuvant ICB combined with cytotoxic chemotherapy has shown a significantly higher rate of pathologic regression of viable tumors compared with cytotoxic chemotherapy alone. To confirm this, an early signal of OS benefit has been shown in a selected population, with programmed death ligand 1 expression ≥50%. Furthermore, applying ICB both pre- and post-surgery enhances its clinical benefits, as is currently under evaluation in ongoing phase III trials. Simultaneously, as the number of available perioperative treatment options increases, the variables to be considered for making treatment decisions become more complex. Thus, the role of a multidisciplinary team-based treatment approach has not been fully emphasized. This review presents up-to-date pivotal data that lead to practical changes in managing resectable NSCLC. From the medical oncologist's perspective, it is time to dance with surgeons to decide on the sequence of systemic treatment, particularly the ICB-based approach, accompanying surgery for operable NSCLC.

Current Treatment Landscape for Early Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and is characterized by an aggressive nature and a high rate of recurrence despite neoadjuvant and adjuvant chemotherapy. Although novel agents are constantly being introduced for the treatment of breast cancer, conventional cytotoxic chemotherapy based on anthracyclines and taxanes is the mainstay treatment option for TNBC. Based on CTNeoBC pooled analysis data, the achievement of pathologic CR (pCR) in TNBC is directly linked to improved survival outcomes. Therefore, the treatment paradigm for early TNBC has shifted to neoadjuvant treatment, and the escalation of neoadjuvant chemotherapy to improve the pCR rate and the addition of post-neoadjuvant chemotherapy to control the residual disease have been investigated. In this article, we review the current treatment landscape for early TNBC, from standard cytotoxic chemotherapy to recent data on immune checkpoint inhibitors, capecitabine, and olaparib.

ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness

Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.

Beyond targeting amplified MDM2 and CDK4 in well differentiated and dedifferentiated liposarcomas: From promise and clinical applications towards identification of progression drivers.

Well differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are tumors of the adipose tissue poorly responsive to conventional cytotoxic chemotherapy which currently remains the standard-of-care. The dismal prognosis of the DDLPS subtype indicates an urgent need to identify new therapeutic targets to improve the patient outcome. The amplification of the two driver genes MDM2 and CDK4, shared by WDLPD and DDLPS, has provided the rationale to explore targeting the encoded ubiquitin-protein ligase and cell cycle regulating kinase as a therapeutic approach. Investigation of the genomic landscape of WD/DDLPS and preclinical studies have revealed additional potential targets such as receptor tyrosine kinases, the cell cycle kinase Aurora A, and the nuclear exporter XPO1. While the therapeutic significance of these targets is being investigated in clinical trials, insights into the molecular characteristics associated with dedifferentiation and progression from WDLPS to DDLPS highlighted additional genetic alterations including fusion transcripts generated by chromosomal rearrangements potentially providing new druggable targets (e.g. NTRK, MAP2K6). Recent years have witnessed the increasing use of patient-derived cell and tumor xenograft models which offer valuable tools to accelerate drug repurposing and combination studies. Implementation of integrated “multi-omics” investigations applied to models recapitulating WD/DDLPS genetics, histologic differentiation and biology, will hopefully lead to a better understanding of molecular alterations driving liposarcomagenesis and DDLPS progression, as well as to the identification of new therapies tailored on tumor histology and molecular profile.