Standard Chemotherapy Regimens Research Articles

CD7 targeted "off-the-shelf" CAR-T demonstrates robust in vivo expansion and high efficacy in the treatment of patients with relapsed and refractory T cell malignancies.

T-cell acute lymphoblastic leukemia (T-ALL) represents an area of highly unmet medical needs. Once relapsed, patients have limited treatment options and poor prognosis. T-ALL antigens such as CD7 is extensively expressed in normal T cells and natural killer (NK) cells, and extending the success of CAR-T therapy to T cell malignancies was challenged by CAR-T cell fratricide, high production cost, and potential product contaminations. GC027 is an "off-the-shelf" allogeneic CD7 targeted CAR-T therapeutic product for T cell malignancies. It demonstrated superior cell expansion and antileukemia efficacy in mouse xenograft model. In our previous study, we observed promising efficacy results in the first two relapsed and refractory(R/R) T-ALL patients treated with GC027. In the expanded study, 11 out of 12 patients had rapid eradication of T-lymphoblasts and reached complete response within 1-month after GC027 infusion. GC027 cells expanded quickly beginning at infusion and reached to peak around 5-10 days after infusion. For most patients with a response(9/11), GC027 could not be detected via flow cytometry or qPCR 4 weeks after infusion. One patient had progression free survival of >3 years. With manageable toxicity profile, GC027 demonstrated superior clinical efficacy to standard chemotherapy regimens in (R/R) T cell malignancies.

Clinicopathologic Impact of NANOG, ZEB1, and EpCAM Biomarkers on Prognosis of Serous Ovarian Carcinoma.

Serous ovarian carcinoma (SOC) is a biologically heterogeneous with different genomic and molecular profiles, beside clinical response to the chemotherapy with subsequent in obstacles in starting unified, acceptable treatments and so we assess immunoexpression of Nanog, ZEB1, and EpCAM in SOC. In this study, the immunoexpression of Nanog, ZEB1, and EpCAM was studied in 60 cases of SOC. Overall survival (OS), disease-free survival (DFS) data and response to chemotherapy were analyzed. NANOG was immunostained in 65% of the cases with a significant association with tumor grade, lymph node metastasis, and FIGO stage (p < 0.001 for each). ZEB1 showed moderate- high expression in 58.3% of the cases with significant up-regulation of ZEB1 expression with SOC grade, nodal metastasis, and SOC FIGO stage (p<0.001). EpCAM revealed high expression in 60% of the cases with significant association with higher grade, nodal metastasis, and advanced stage (p < 0.001 for each). Up-regulation of Nanog was significantly associated with response to chemotherapy, relapse, shorter OS and DFS (p < 0.001 for each). ZEB1 overexpression exhibited a significant association with response to chemotherapy (p= 0.012), relapse, shorter OS and DFS (p<0.001 for each). Moreover, the high EpCAM had a significant association with response to chemotherapy (p= 0.043), relapse (p < 0.001) shorter OS (p=0.006) and DFS (p< 0.001). Up-regulation of Nanog and ZEB-1 and EpCAM perhaps promote an aggressive SOC with a high risk of relapse and unfavorable response to standard chemotherapy regimen.

Blastic plasmacytoid dendritic cell neoplasm: a short review and update

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic neoplasm (less than 1% of primary cutaneous lymphomas and acute leukemia) with a highly aggressive clinical course and frequent skin, bone marrow and central nervous system (CNS) involvement. Despite a frequent initial response to chemotherapy, relapses with eventual leukemic dissemination are extremely common, leading to poor outcomes and a median overall survival (OS) ranging from 8 to 14 months in first line setting, with standard combination chemotherapy regimens. The skin is the first affected site (in almost 90% of patients) where BPDCN may remain confined for weeks or even months (sanctuary?) until a rapid second step with multiorgan involvement occurs. Therefore, it is of uppermost importance to suspect and recognize early skin lesions and to perform and report a skin biopsy as soon as possible. A multidisciplinary approach with coordination among dermatologists, pathologists and hematologists is definitively crucial in diagnosis and management of BPDCN.

Blastic plasmacytoid dendritic cell neoplasm: a short review and update

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic neoplasm (less than 1% of primary cutaneous lymphomas and acute leukemia) with a highly aggressive clinical course and frequent skin, bone marrow and central nervous system involvement. Even though there is often an early response to chemotherapy, leukemic dissemination relapses are very common and result in poor outcomes, with a median overall survival of 8 to 14 months in the first-line setting using standard combination chemotherapy regimens. Almost 90% of patients experience skin involvement as their initial site of infection, where BPDCN may stay restricted for weeks or even months until a swift secondary phase involving multiple organs takes place. Consequently, it is crucial to suspect and identify early skin lesions, as well as to conduct and report a skin biopsy as soon as possible. In order to diagnose and treat BPDCN, a multidisciplinary strategy involving collaboration between pathologists, hematologists, and dermatologists is unquestionably essential.

Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma.

Introduction: Treatment of relapsed or refractory acute myeloid leukemia (R/R AML) and myeloid sarcoma (MS) has presented challenges for decades. Studies on selinexor in combination with various standard or intensive chemotherapy regimens for the treatment of R/R AML have demonstrated promising results. This study aimed to evaluate the efficacy and safety of chemotherapy-free or low-dose chemotherapy regimens with selinexor for R/R AML and MS patients. Methods: Ten patients with R/R AML or MS who received chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor at Tongji Hospital from October 2021 to August 2022 were included in this study. The primary endpoint was overall response rate (ORR) and secondary endpoints included complete remission (CR), CR with incomplete hematological recovery (CRi), partial remission (PR), transplantation rate, and safety. Results: All patients were evaluable for response, achieving CR in four (40.0%) patients and CRi in two (20.0%) patients for a total CR/CRi of 60.0%. The ORR was 80.0% when patients with PR were included. Five (50.0%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with selinexor-containing regimens. At the end of the follow-up, seven (70.0%) patients were alive, and three patients died of transplant-related complications or disease progression. The most frequently reported nonhematologic adverse events (AEs) in patients were grade 1 or 2 asymptomatic hyponatremia. Conclusion: The chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor for R/R AML are feasible and tolerable and provide an opportunity for patients to receive transplantation.

Coq10 for preventing cardiotoxicity in breast cancer patients treated with trastuzumab.

Trastuzumab is a successful treatment option for HER2-positive breast cancer, but a decline in left ventricular ejection fraction (LVEF) and an increase in inflammatory and cardiac enzyme biomarkers can lead to cessation and termination of therapy. This study aimed to investigate the ability of Coenzyme Q10 (Coq10) to avoid these adverse effects. The study included 100 female patients with HER2+ (HER2+3 or amplified gene) breast cancer. All patients underwent standard adjuvant chemotherapy regimens, which involved a four-cycle treatment of Adriamycin, Cyclophosphamide, Docetaxel, and an initial 8 mg/kg loading dose of trastuzumab, followed by a year of 6 mg/kg maintenance doses every three weeks. One group of 50 patients received trastuzumab and a placebo, while the other 50 were given trastuzumab and CoQ10 for a full year. The CoQ10-treated group exhibited a statistically significant decrease in levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL6), soluble toll-like receptor 4 (sTLR4), and cardiac troponin I (cTnI) compared to the control group (p<0.05). However, there was no significant difference in the mean F2-isoprostane levels between the treated and the control groups at any data collection point. Furthermore, the CoQ10-treated group experienced a significant reduction in the decline of EF levels compared to the control group at all stages except for baseline. According to our findings, Coenzyme Q10 protected patients with HER2+3 breast cancer from the cardiotoxicity of trastuzumab by increasing ejection fraction and decreasing inflammatory biomarkers and cardiac enzyme levels.

Experience of using talazoparib in the aggressive course of BRCA2-associated triple-negative breast cancer: a clinical observation

The median overall survival for patients with metastatic triple-negative breast cancer is about 12-14 months. Chemotherapy has been the only treatment option for this tumour subtype for a long time, irrespective of immunological and genetic characteristics. Straightforward therapy algorithms have not been defined, and the optimum sequencing of chemotherapy regimens is left to the discretion of the attending physician. Today, impressive findings from clinical studies on the use of immunotherapy and targeted therapy for cancer using PARP inhibitors reflect in current guidelines, raising the chances of patients to prolong life and maintain its high quality. Thus, the use of immunotherapy as first-line treatment of PD-L1-positive tumours allowed to significantly increase the overall survival of patients for the first time in many years. And the use of PARP inhibitors in carriers of BRCA1/2 germline mutations not only significantly prolongs progression-free survival, but also improves quality of life versus standard chemotherapy regimens. The benefit is also observed in patients with an aggressive course of the disease such as damage to the visceral organs and the central nervous system. The presence of BRCA1/2 germline mutations in the genes, damage to the CNS and visceral organs is associated with an extremely unfavourable prognosis and a significant decline in life expectancy. However, a high-quality diagnosis before initiation of treatment, creating proper treatment plans and the use of modern opportunities can improve the outcomes of treatment. The article discusses possible treatment options for metastatic TNBC, reflects current guidelines on the use of immuno- and targeted therapy. A clinical case report of the treatment of a patient with a significantly aggravated history and an aggressive course of TNBC is presented. The patient with visceral metastases, brain damage and early progression after primary treatment has been receiving therapy for two years, while maintaining a satisfactory quality of life.

The Unmet Diagnostic and Treatment Needs in Large Cell Neuroendocrine Carcinoma of the Lung.

Large cell neuroendocrine carcinoma of the lung (LCNEC) is currently classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis of LCNEC is mainly based on the microscopic appearance of the tumor cells, the mitotic rate, the amount of intra-tumoral necrosis, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery is still the best option for resectable, stage I-IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pathology-driven chemotherapy approach. Encouraging outcomes have also been reported for immunotherapy and targeted therapy, but the real impact of these strategies is still being determined in the absence of adequate prospective clinical trials. The current paper scrutinized the epidemiology, reviewed the reliability of pathologic diagnosis, discussed the need for molecular subtyping, and reviewed the heterogeneity of treatment algorithms in LCNEC.

Treatment Problems In Triple Negative Breast Cancer

Background: Breast cancer ranks second on the list of common diseases worldwide. It causes many deaths in the United States and Europe, second only to lung cancer. Triple-negative breast cancer (TNBC) does not express Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epithelial Receptor (HER2). It represents 24% of new cases of all breast cancer, and its incidence increases yearly. TNBC is a hormone-resistant breast cancer, so no current standard therapy exists. This article aims to explore regimen-resistant and troubleshooting treatment responses in TNBC cases. The method of writing this article is a literature review of studies using the keywords triple-negative breast cancer treatment and regimen, which are limited to only the most recent articles, 2012-2022, using search engines from PubMed, Science Direct, and Google Scholar. Results: There is no definitive therapy for the triple-negative breast cancer subtype, in which the TNBC type has no target receptor. Chemotherapy is the SOC of TNBC for early stage treatment. For late-stage and relapsed TNBC, however, chemotherapy is no longer the first choice. Currently there is no standard chemotherapy regimen that can be given to patients who experience relapse after chemotherapy because they will have a short response and lead to metastases. Some studies have shown that chemotherapy gives a better response, but the prognosis of TNBC remains poor. TNBC has different responses to therapy. TNBC showed a good response to combination chemotherapy along with pembrolizumab, capecitabine, olaparib, and radiotherapy, compared to chemotherapy by itself. Surgical therapy, such as Breast-Conserving Surgery (BCS), does not improve better prognosis in TNBC patients. Conclusions: Combining pembrolizumab, olaparib, capecitabine, and radiotherapy with chemotherapy increased survival rates compared to chemotherapy only.

A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment.

TPS12143 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, painful, and debilitating side effect of many standard chemotherapy regimens. CIPN symptoms include pain, paresthesia, and muscle weakness, and patients may exhibit functional decline and lower quality of life. Our prior study showed more than half of breast cancer survivors experience persistent CIPN up to a mean duration of 5.6 years, which is associated with a doubled fall risk. Identifying non-pharmacological approaches to reduce CIPN symptoms and improve cancer survivors’ outcomes is urgently needed. Yoga is a meditative movement therapy that includes stretching, and flexibility and balance training. Our pilot study (NCT03292328) demonstrated that yoga reduced CIPN-related symptoms, and improved quality of life and functional reach scores compared to waitlist control. We hypothesize that yoga can reduce CIPN symptoms, improve function, and reduce the risk of falls. Methods: We are conducting a three-arm randomized education and usual care-controlled trial in cancer survivors with chronic CIPN pain at Memorial Sloan Kettering Cancer Center (MSK), New York, NY. Participants in the intervention arm will receive twice-weekly one-hour Hatha yoga classes taught virtually by MSK instructors and practice yoga at home daily for eight weeks. Participants in the education control arm will receive one-hour virtual education classes twice per week taught by an MSK instructor for eight weeks. Participants in the usual care arm will continue their usual care for CIPN for eight weeks. The primary endpoint is the Brief Pain Inventory-Short Form average pain item at weeks 8 and 24. Secondary outcomes include the Neuropathic Pain Scale, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, Patient-Reported Outcomes Measurement Information System Global Health, Brief Fatigue Inventory, Insomnia Severity Index, Hospital Anxiety and Depression Scale, Quality of Life Questionnaire of CIPN twenty-item scale, functional assessments, and quantitative sensory testing at weeks 0, 4, 8, 12, 18, and 24. Eligibility criteria include: 1) Moderate-to-severe CIPN pain, defined by a score of 4 or greater on a 0-10 numerical rating scale; 2) completion of neurotoxic chemotherapy at least three months prior; 3) no changes in anti-neuropathy medications within three months of enrollment; and 4) changes in balance and functionality. As of February 2023, we have accrued 64 of our total target of 268 participants. We anticipate completing accrual in March 2025. We have 35 participants in the yoga intervention, 15 participants in education control, and 14 participants in usual care control. The majority (89%) of participants are female and 11% are male. 78% of our participants are white, 16% are black or African American, 1% are Asian, and 5% identify as more than one race. Clinical trial information: NCT05121558 .

Application of a contralateral esophageal-sparing technique to reduce radiation esophagitis in limited-stage small cell lung cancer treated with twice-daily radiotherapy and concurrent chemotherapy.

e20644 Background: Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. Methods: We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. Results: We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p &lt; 0.001). The CE’s median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. Conclusions: By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.

Assessing the efficacy and safety of DEB-BACE combined with intravenous chemotherapy for the treatment of intermediate to advanced lung adenocarcinoma after progression of targeted drug resistance.

8555 Background: To compare the efficacy and safety of drug-eluting bead bronchial arterial chemoembolization (DEB-BACE) combined with intravenous chemotherapy versus systemic intravenous chemotherapy for intermediate to advanced lung adenocarcinoma with positive driver genes after progression of targeted therapy. Methods: A total of 131 patients with intermediate to advanced lung adenocarcinoma were retrospectively recruited from 2018-2022 and divided into Group A (standard chemotherapy regimen, N=62) and Group B (DEB-BACE and intravenous chemotherapy, N=69). The short-term efficacy, hemoptysis remission rate, dyspnea remission rate, and incidence of adverse effects were compared between the two groups using the χ2 test. Survival estimates were performed by Kaplan-Meier, and a Log-rank test was performed to examine survival differences between groups. Results: The three-month disease control rate (DCR: 82.6% vs 58.1%) and objective remission rate (ORR: 60.9% vs 38.7%) were better in group B than in group A (both P&lt;0.05). Median progression-free survival (PFS, 10.0 vs 7.9 months) and median overall survival (OS, 33.0 vs 18.0 months) were better in group B than in group A (both P &lt; 0.05). The PFS rates at 6, 12, and 24 months were 67.3%, 40.8%, and 0.0% and 54.1%, 23.2%, and 0.0% in groups B and A, respectively; and the OS rates at 6, 12, and 24 months were 100%, 95.7%, 72%, 88.6%, 66.1%, and 21.8% in group B and group A, respectively, with statistically significant differences (P &lt; 0.05). Within one month after treatment, group B had better hemoptysis relief (83.3% vs. 20.0%) and dyspnea relief (57.5% vs. 30.0%) than group A (both P &lt; 0.05). During the follow-up period, the incidence of adverse reactions was significantly lower in group B than in group A (P &lt; 0.05). Conclusions: For patients with intermediate to advanced lung adenocarcinoma who have failed to progress on targeted therapy, DEB-BACE combined with intravenous chemotherapy has shown superior efficacy and survival benefit and lower adverse effects, while significantly improving patients' symptoms of hemoptysis and dyspnea, with important application prospects.

Pegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin as first-line treatment for Chinese patients with ovarian cancer: A multi-center, randomized, open-label trial.

5556 Background: Paclitaxel combined with carboplatin is a standard first-line chemotherapy regimen for ovarian cancer. This study was designed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin (CD) compared with paclitaxel plus carboplatin (CP) as first-line treatment for epithelial ovarian cancer (EOC). Methods: Patients with stage IC to IV EOC, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this open-label, randomized controlled trial at 20 centers in China. Patients were randomly assigned 1:1 to CD group (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) or CP group (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for 3-6 cycles. The primary end point was progression free survival (PFS); secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between March, 2019 to December, 2021, 395 patients were enrolled, of whom 391 patients were analyzed (195 assigned to CD, 196 to CP). Baseline characteristics were balanced between the two treatment groups. The median follow-up was 21.6 months for the CD group and 22.5 months for the CP group. There was no significant difference in PFS between the two arms (P=0.516); the median PFS was 28.1 months and 30.1 months in the CD and CP arms, respectively. OS data were immature at data cutoff, with a total of 26 deaths in the two treatment groups. In patients with at least one measurable lesion at baseline, ORR was 65.5% in the CD arm and 66.2% in the CP arm (P= 0.941); DCR was 74.1% and 73.8% in the CD and CP arms, respectively (P= 0.971). Among patients who were evaluable by GCIG CA125 criteria, CA125 response was obtained in 86.0% and 88.5% of patients in the CD and CP arms, respectively (P=0.560). More frequent grade 1 to 3 alopecia (32.1% vs 12.3%) and neurotoxicity (20.4% vs 0%) were observed in the CP arm; more hand-foot syndrome (grade 1 to 3, 10.8% vs 2.6%), and oral mucositis (grade 1-3, 12.8% vs 5.1%) in the CD arm. Conclusions: The efficacy of CD regimen is comparable to that of CP, with less alopecia and neurotoxicity. CD may be an alternative first-line treatment for EOC. However, survival data are not yet mature, and longer follow-up is needed. Clinical trial information: NCT03794778 .

Neoadjuvant single-dose trilaciclib prior to combination chemotherapy in patients with early triple-negative breast cancer: Safety, efficacy, and immune correlate data from a phase 2 study.

603 Background: Trilaciclib, an intravenous CDK4/6 inhibitor, induces transient G1 cell cycle arrest. In preclinical studies, trilaciclib demonstrated immune-modulating effects by enhancing T-cell activation, favorably altering the tumor microenvironment (TME), and improving long-term immune surveillance. Preliminary data from this phase 2, single-arm, open-label study of neoadjuvant trilaciclib in triple-negative breast cancer (TNBC; NCT05112536) showed that single-dose trilaciclib increased CD8+ T-cell/Treg ratios within the TME. Here, we combine immune analysis with clinical outcomes to identify correlates of treatment response. Methods: Patients (pts) with early-stage TNBC received single-dose trilaciclib followed by trilaciclib + dose-dense anthracycline/cyclophosphamide and taxane (AC/T). Per investigator discretion, pts received pembrolizumab (pembro) 400 mg Q6W from cycle 1 and/or carboplatin (carbo) AUC 1.5 QW from cycle 5. Tumor biopsies and blood samples were collected prior to treatment, 7 days post single-dose trilaciclib, and during surgery, with an additional blood sample at cycle 2. PDL1 status was assessed per Ventana SP142 assay (positive immune cell score ≥ 1%). The primary objective is to evaluate the immune-based mechanism of action of single-dose trilaciclib. Results: As of January 3, 2023, 18/24 pts had completed treatment and/or had definitive surgery; 1 pt with neuroendocrine features discontinued due to disease progression. Median age was 57 years. At diagnosis, 79% of pts had stage II tumors (88% with ductal carcinoma; 38% with PDL1+ tumors). 18 pts received pembro + carbo, 3 pts pembro only, and 3 pts carbo only. Common treatment-related adverse events (TRAEs) were fatigue (79%), nausea, (67%), alopecia (67%), and neutropenia events (63%); 42% of pts had grade 3/4 neutropenia events. 4 serious TRAEs occurred in 2 (8%) pts: pembro-related colitis and hypertransaminasemia, trilaciclib/paclitaxel-related urosepsis, and AC-related febrile neutropenia. Response data were available for 15 pts; pathologic complete response (pCR) was observed in 7 (47%) pts, with pCR rates of 86% vs 13% for pts with PDL1+ vs PDL1– tumors, respectively. Immune analysis of the TME post trilaciclib monotherapy demonstrated several pCR-related features, such as increased stromal tumor-infiltrating lymphocytes and granzyme B+ cells. Correlative blood analysis revealed increased circulating baseline CD8+ T cells in pts achieving pCR. Conclusions: Safety and tolerability data are encouraging for trilaciclib in combination with AC/T ± pembrolizumab ± carboplatin in the neoadjuvant setting for early-stage TNBC. Preliminary efficacy data align with standard neoadjuvant chemotherapy regimens. Final pCR data from all pts and immune correlates from tumor and blood samples will be presented. Clinical trial information: NCT05112536 .

Oral capecitabine or tegafur/gimeracil/oteracil as induction and adjuvant/maintenance chemotherapy in the management of stage III-IVb nasopharyngeal carcinoma: A systematic-review and meta-analysis.

e18000 Background: According to practice guidelines, concurrent chemoradiotherapy or induction chemotherapy with subsequent chemoradiotherapy is the recommended regimen for Stage III-IV NPCA. Unfortunately, local and distant recurrence continue to be primary reasons for treatment failure. To improve existing treatment regimens, replacing infusional 5-fluorouracil with oral fluoropyrimidine equivalents was suggested due to lower hazard of death and progression. In this meta-analysis we will be investigating the use of oral fluoropyrimidines, namely capecitabine and tegafur/gimeracil/oteracil, to elucidate their efficacy and effectiveness in Nasopharyngeal Carcinoma (NPCA) compared to standard chemotherapy regimens. Methods: A literature search of PubMed, Cochrane CENTRAL, and ClinicalTrials.gov was done in compliance with the PRISMA-P guidelines. After screening 908 records and selecting 32 articles for full-text assessment, 29 articles were included in the systematic-review and 15 in the meta-analysis. Outcomes were assessed for quality of evidence using a modified GRADE criteria. Overall Survival (OS) was assessed as the primary endpoint. Secondary outcomes were Progression Free Survival (PFS), Disease Free Survival (DFS), Distant Metastasis Free Survival (DMFS) and Locoregional Recurrence Free Survival (LRFS). Risk Ratio (RR) was used as the measure of association for all outcomes. Significance was assessed using p-values and I2 for the presence of heterogeneity. All pooled outcomes were assessed with 95% confidence intervals (CI). Statistical analysis was done using Stata and Review Manager 5. Results: The PFS RR of the adjuvant/maintenance group and induction group, respectively, were 0.53 [95%CI 0.38, 0.72]; I2 = 41% (p &lt; 0.001) and 0.59 [95%CI 0.37, 0.95]; I2 = 0% (p = 0.03). DFS, LRFS, and DMFS of the adjuvant/maintenance group were 0.61 [95%CI 0.44, 0.83]; I2 = 0% (p = 0.002), 0.48 [95%CI 0.28, 0.83]; I2 = 0% (p = 0.008) and 0.67 [95%CI 0.44, 1.01]; I2 = 0% (p = 0.06), respectively. The induction group's LRFS and DMFS, respectively, were 0.55 [95%CI 0.37, 0.82] (p = 0.004); I2 = 0% and 0.60 [95%CI 0.40, 0.91]; I2 = 25% (p = 0.02). The OS for the adjuvant and induction group were 0.51 [95%CI 0.38, 0.69]; I2 = 21% (p &lt; 0.001) and 0.72 [95%CI 0.52, 1.00]; I2 = 14% (p = 0.05), respectively. Conclusions: Based on “Low to Moderate” levels of evidence, induction oral fluoropyrimidine-containing regimens are associated with significantly higher 2-3 year PFS and 3-5 year LRFS as well as DMFS with equivalent 2-5 year OS in previously-untreated Stage III-IVB NPCA. Meanwhile, adjuvant/maintenance oral fluoropyrimidine-containing regimens lead to significantly higher 2-5 year OS and 3-5 year PFS, DFS, DMFS and LRFS compared to induction CCRT alone in previously-untreated Stage III-IVB NPCA.

Review of Current Systemic Therapy and Novel Systemic Therapy for Pancreatic Ductal Adenocarcinoma.

This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy. A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy. The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field. While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

BackgroundChemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance.MethodsWe established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism.ResultsHigh-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy.ConclusionsIrbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature

BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7–14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4–4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

Carboplatin and irinotecan (CI) vs. carboplatin and etoposide (CE) for the treatment of extended-stage small-cell lung cancer in an elderly population: A phase II/III randomized control trial

ObjectivesCisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC. Materials and methodsThis was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1–3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles. ResultsIn total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3–13.7) vs. 13.2 (95% CI, 11.1–14.6) months (HR, 0.85 (95% CI, 0.65–1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0–4.7) vs. 4.9 (95% CI, 4.5–5.2) months (HR, 0.85 (95% CI, 0.66–1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm). ConclusionsThe CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.

Abstract PL02-04: Malignancies in People with HIV: Successes and Challenges at the Intersection of Virology, Immunology, and Oncology

Abstract PL02-04: Malignancies in People with HIV: Successes and Challenges at the Intersection of Virology, Immunology, and Oncology