Platinum-based Neoadjuvant Chemotherapy Research Articles

Pooled analysis of NeoCARH and NeoCART trials: patient-reported outcomes in patients with early-stage breast cancer receiving platinum-based or anthracycline-based neoadjuvant chemotherapy.

Anthracycline-based or platinum-based neoadjuvant chemotherapy belongs to the standard treatment for early-stage breast cancer (EBC) that is either triple-negative or human epidermal growth factor receptor 2 positive (HER2 +). Currently, there is a paucity of data comparing their impact on health-related quality of life (HRQoL). Triple-negative or HER2 + EBC from our two prospective randomized controlled trials, neoCARH and neoCART, were divided into two groups based on the neoadjuvant chemotherapy regimens they received: anthracycline-based or platinum-based group. HRQoL was the exploratory endpoint in these two trials, which was assessed using the European Organization for Research and Treatment of Cancer Quality of Life-Core30 and Breast23 questionnaires. The primary variable of interest was the C30 summary score (C30-SumSc). Assessments were carried out at baseline, after neoadjuvant chemotherapy, and 1year and 2years after diagnosis. The mean questionnaires' compliance rate was 95.0%. After neoadjuvant chemotherapy, 210 patients had evaluable HRQoL data, the mean least square change from baseline for the platinum-based group was - 15.997 (95% confidence interval (CI): - 17.877 to - 14.117), and it was - 20.156 (95% CI: - 22.053 to - 18.258) for the anthracycline-based group (difference: 4.159, 95% CI: 1.462 to 6.855, P = 0.003, minimal important difference = 3). For the majority of the domains of interest assessed by the C30 and BR23 questionnaires, the platinum-based group demonstrated superior outcomes in comparison to the anthracycline-based group. Patients receiving platinum-based or anthracycline-based regimens both experienced worsened HRQoL after neoadjuvant chemotherapy; however, the former provided relatively better HRQoL compared with the latter. ClinicalTrials.gov: NCT03140553. Registered 4 May 2017 (neoCARH). NCT03154749. Registered 16 May 2017 (neoCART).

Abstract 3702: Dissecting circulating tumor cells phenotype in a cohort of locally advanced non-small cell lung cancer patients undergoing neoadjuvant chemotherapy

Abstract Background: Platinum-based neoadjuvant chemotherapy (pb-NACT) is the primary treatment approach for locally advanced non-small cell lung cancer (LA-NSCLC), despite offering only a limited overall survival (OS) gain. Cisplatin-induced cell damage has been shown to activate the SDF-1/CXCR4 axis in preclinical models of NSCLC, resulting in the recruitment of a cell subset co-expressing the stemness marker CD133 and CXCR4 (SDF-1 receptor) at distant sites. These cells, known as metastasis-initiating cells (MIC), exhibit prometastatic activity. By longitudinally monitoring circulating tumor cells (CTC) in the blood of LA-NSCLC patients (pts) undergoing pb-NACT, our objective is to assess the potential prognostic significance of CTC number and phenotype. Methods: Between February 2019 and August 2023, a total of 61 pts with LA-NSCLC undergoing pb-NACT, were included in the study. Blood samples were obtained at baseline (T1), post-pb-NACT (T2), and post-surgery (T3) for the characterization of CTC, including total CTC, CXCR4+CTCs, and CXCR4+CD133+ MIC. This characterization utilized a validated marker-independent strategy combining Parsortix and DEPArrayTM technologies. Logistic regression models were employed to examine the association between CTC subsets and the response to pb-NACT (Disease Control Rate [DCR], Overall Response Rate [ORR]), while Cox-regression models were used to assess their association with survival endpoints (event-free survival [EFS], OS, disease-free survival [DFS]). Results: Out of the 61 enrolled patients, 34 had available CTC data for analysis. In this population, DCR was 64.7%, and the ORR 29.4%. Surgery was performed in 14 pts (41.2%). At baseline (T1), elevated levels of CXCR4+CTCs were linked to a lower DCR (10 vs 3/mL, odds ratio [OR]=0.02, 95% confidence interval [CI]: 0-0.40, p=0.008), as well as shorter EFS (10 vs 3/mL, HR=4.20, 95% CI: 1.84-9.58, p=0.002) and OS (10 vs 3/mL, HR=3.14, 95% CI: 1.25-7.88, p=0.004). At the post- CT time point (T2), higher levels of MIC were associated with shorter EFS (3 vs 0/mL, HR=1.41, 95% CI: 1.00-1.99, p=0.047) and OS (3 vs 0/mL, HR=1.55, 95% CI: 1.03-2.34, p=0.035). Although the sample size was limited, a higher number of MIC at the post-surgery time point (T3) showed a trend toward reduced DFS. Discussion: CTC could serve as a novel biomarker for assessing the effectiveness of pb-NACT in LA-NSCLC. Elevated levels of CXCR4+CTC both at baseline and after pb-NACT, along with increased MIC post-pb-NACT and post-surgery, indicate unfavorable prognostic factors for survival. Specifically, a higher baseline of CXCR4+CTCs may be linked to a suboptimal response to treatment, suggesting the potential need for treatment intensification in patients exhibiting elevated CXCR4+CTC baseline levels. Citation Format: Rita Leporati, Teresa Beninato, Sara Iadecola, Chiara Andreon, Fabio Murianni, Melissa Balsamo, Antonia Martinetti, Benedetta Lombardi Stocchetti, Laura Mazzeo, Sara Manglaviti, Mario Occhipinti, Marta Brambilla, Arsela Prelaj, Claudia Proto, Rosalba Miceli, Luca Roz, Gabriella Sozzi, Filippo De Braud, Giuseppe Lo Russo, Giulia Bertolini. Dissecting circulating tumor cells phenotype in a cohort of locally advanced non-small cell lung cancer patients undergoing neoadjuvant chemotherapy [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 3702.

118P Role of PD-L1 and pathological complete response (pCR) with neoadjuvant (NEO) or perioperative (PERIOP) immune-checkpoint inhibitors (ICI) and platinum-based chemotherapy (PCT) in resectable non-small cell lung cancer (NSCLC): A systematic review and metanalysis

118P Role of PD-L1 and pathological complete response (pCR) with neoadjuvant (NEO) or perioperative (PERIOP) immune-checkpoint inhibitors (ICI) and platinum-based chemotherapy (PCT) in resectable non-small cell lung cancer (NSCLC): A systematic review and metanalysis

Different Chemotherapy Regimens and Pathologic Complete Response in Triple-Negative Breast Cancer: An Updated Network Meta-Analysis of Phase 3 Trials.

Background and Objectives: Currently, the standard treatment for non-metastatic triple-negative breast cancer (TNBC) consists of a systemic neoadjuvant (or perioperative) anthracycline plus taxane-based chemotherapy, delivered either sequentially or concomitantly. We performed a network meta-analysis (NMA) to compare the relative efficacy of different neoadjuvant treatments for TNBC in terms of pathologic complete response (pCR). Materials and Methods: The MEDLINE, Embase, and Cochrane databases were searched from database inception to 1 November 2023. Randomized clinical trials were used that enrolled adults with stage I-III TNBC and provided data on pCR defined as residual ypT0/TisN0M0. Between-group comparisons were estimated using risk ratios (RRs) with 95% credible intervals (95% CrIs). The primary outcome was the pCR rate. Results: 1129 citations were screened, and 12 randomized clinical trials were included. In Bayesian comparisons, all regimens, except anthracycline/taxanes plus gemcitabine or capecitabine, resulted in a higher pCR than the standard regimen in both direct and indirect comparisons. In particular, immunotherapy-based regimens resulted in more than double the pCR compared to historical regimens (RR = 2.3, 95% CI 1.9-2.9) and ranked as being the optimal regimen with a probability of 97%. Disease-free survival was better for immune checkpoint inhibitor-based chemotherapy (HR = 0.36, 95% 1.21-2.09) than for historical regimens. Conclusion: This meta-analysis confirmed that incorporating immunotherapy with neoadjuvant platinum-based chemotherapy is the best option to guarantee remarkable pathologic downstaging and improve clinical outcomes.

Neoadjuvant Platinum-Based chemotherapy and lymphadenectomy for penile cancer: an international, Multi-Institutional, Real-World study.

This study investigated the efficacy and safety of neoadjuvant chemotherapy (NAC) for locally advance penile squamous cell carcinoma (PSCC), for which current evidence is lacking. Included patients had locally advanced PSCC with clinical lymph node metastasis treated with at least one dose of NAC prior to planned consolidative lymphadenectomy. Objective response rates (ORR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events (trAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 209 patients received NAC for locally advanced and clinically node-positive PSCC.The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 TrAEs occurred in 35 (17%) patients, and no treatment related mortality was observed. 201 (97%) completed planned consolidative lymphadenectomy. During follow up, 106 (52.7%) patients expired, with a median OS of 37.0 months (95% CI 23.8-50.1), and median PFS of 26.0 months (95% CI 11.7-40.2). ORR was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to NAC had a longer median OS (73.0 vs 17.0 months, p < .01) compared to those who did not. The lymph-node pathologic complete response rate (ypN0) was 24.8% in the cohort. NAC with lymphadenectomy for locally advanced PSCC is well tolerated and active to reduce the disease burden and improve long term survival outcomes.

Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.

To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-β, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-β and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. NACT increased the expression of STING, IFN-β and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. NACT stimulates STING/IFN-β pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.

The impact of germline BRCA pathogenic variants in locally advanced, triple negative breast cancer treated with platinum-based neoadjuvant chemotherapy

BackgroundWhether germline BRCA (gBRCA) pathogenic variants (PV) affect prognosis of women with triple negative breast cancer (TNBC) and whether it has implications for treatment decisions in the neoadjuvant setting is unclear.MethodsThis is a retrospective two-center cohort study comprising all women with early stage TNBC who have completed genetic testing and were treated with neoadjuvant dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and carboplatin. All eligible patients treated between 10.2014 and 3.2020 were included. Data on clinico-pathological, pathological response, overall survival (OS) and disease-free survival (DFS) were evaluated. Differences in clinico-pathological features and outcomes were analyzed according to gBRCA status.ResultsSixty-four women were included in the final analysis, of which 31 had gBRCA PV (gBRCA carriers) and 33 were gBRCA wild-type. Clinico-pathological characteristics were similar between both groups. The odds for pathological complete response (pCR) were significantly higher in gBRCA carriers (74.2%) compared to BRCA wild-type women (48.5%), p = 0.035. At a median follow-up of 30 months, gBRCA carriers had significantly favorable OS (HR = 8.64, 95% CI 1.08–69.21, p = 0.042). The difference in DFS did not reach statistical significance (HR = 7.4, 95% CI 0.91–60.27, p = 0.062). The favorable OS for gBRCA carriers remained significant in multivariate analysis (p = 0.029) and was noted regardless of pathological response (p = 0.018).ConclusionCompared to wild-type, gBRCA carriers with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcomes. These results strengthen the contention that gBRCA status should be considered when tailoring treatment decisions in women with locally advanced TNBC.

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation.

LBA531 Background: Muscle-invasive urothelial carcinoma (MIUC) is an aggressive disease with high relapse rates. Neoadjuvant platinum-based chemotherapy (NAC) is the standard of care in patients (pts) who are cisplatin (Cis)-eligible. However, many pts are Cis-ineligible or have persistent muscle-invasive disease after NAC and surgery. We evaluated pembrolizumab (Pembro) as adjuvant therapy in pts with high-risk MIUC following surgical resection. Methods: The AMBASSADOR study is an open-label, randomized, phase III trial that enrolled pts with histologically confirmed MIUC of the bladder, upper tract, or urethra who (1) had ≥ pT2 and/or pN+ or margins+ at surgery (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) following NAC or (2) ≥ pT3 and/or pN+ or margins+ at surgery without NAC and were either Cis-ineligible or declined adjuvant Cis-based therapy. Pts were registered ≥4 to 16 weeks after surgery and randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The dual primary endpoints were disease-free survival (DFS) and overall survival (OS) with a target sample size of 739 pts and required 387 DFS and 320 OS events for final analysis. Secondary objectives included evaluation of DFS and OS in PD-L1-positive and -negative pts and assessing safety. Here we present the interim DFS and OS results. Results: Between 09/2017 and 08/2021 a total of 702 pts were randomized prior to early closure due to US FDA approval of nivolumab for MIUC pts: 354 pts to Pembro and 348 pts to Obs; 13.0% vs 21.6% withdrew from study without event in the Pembro vs Obs arms, respectively. 74 pts (21%) in the Obs arm received an immune checkpoint inhibitor. Median follow-up was 22.3 months (mos) for DFS and 36.9 mos for OS. The DFS endpoint (based on 319 events needed for interim analysis) crossed the efficacy boundary. Median DFS was 29.0 months (95% confidence interval (CI) 21.8‒not evaluable (NE)) with Pembro and 14.0 months (95% CI 9.7‒20.20) with Obs (hazard ratio (HR) 0.69 [95% CI 0.55–0.87]; p=0.0013). At the interim analysis (n = 257 events), median OS was 50.9 months (95% CI 43.9‒NE) with Pembro and 55.8 months (95% CI 53.3‒NE) with Obs (HR 0.98 [95% CI 0.76–1.26]; p=0.88). Grade 3+ adverse events occurred in 48.4% and 31.8% of pts in the Pembro and Obs arms, respectively. Conclusions: Adjuvant Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs Obs for high-risk MIUC pts after radical surgery. The OS endpoint may have been impacted by pts on the Obs arm receiving a checkpoint inhibitor. Pembro was tolerable with no new safety signals. These results support adjuvant Pembro as a new therapeutic option for pts with MIUC with high risk for recurrence. Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and ctDNA analyses. Clinical trial information: NCT03244384 .

Thromboembolic events associated with neoadjuvant chemotherapy for muscle invasive cancer of the bladder.

586 Background: Patients with muscle invasive bladder cancer who undergo platinum-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy or radiotherapy are at high risk of venous and arterial thromboembolic events (TEE). TEE is associated with delay to radical cancer treatment, significant morbidity and even mortality. This study aimed to document the incidence and characteristics of TEE during NAC and prior to radical treatment. Methods: Retrospective data was collected on all patients in our centre who underwent NAC prior to radical treatment. TEE events were identified based on routine imaging to assess for response to NAC; or imaging based on clinical symptoms developed during (or within 28 days) of NAC but prior to radical treatment. Results: Data was collected on 148 patients between January 2015 and September 2023. Age range: 44 - 82 years, the majority (73.6%) of whom were male. All patients received platinum-based chemotherapy (median 4 cycles). A total of 31 patients (20.9%) developed 35 TEE, including 27 venous events (24 pulmonary emboli and 3 deep venous thromboses), and 8 arterial events (3 aortic thrombus, 4 limb ischaemia, 1 ischemic stroke). Four patients had a venous and arterial TEE. The majority of pulmonary venous TEE were subclinical. Conclusions: Our single-centre study demonstrates that the incidence of TEE during NAC prior to radical treatment for bladder cancer is high. Improved imaging techniques and routine scans post-NAC led to identification of subclinical TEE that require treatment as they are likely to become clinically significant. The high rate of TEE in this patient population is likely to benefit from prophylactic anticoagulation during NAC and should be investigated in future prospective clinical trials.

Adjuvant and neo-adjuvant therapy for non-small cell lung cancer without EGFR mutations or ALK rearrangements.

Surgical resection is the most effective therapeutic option for the cure in early stage resectable non-small-cell lung cancer (NSCLC). However, despite complete resection, up to 70% of patients die within 5 years mainly due to tumor recurrence in extra-thoracic organs. Adjuvant or neoadjuvant platinum-based chemotherapy may improve postoperative survival, but the absolute survival benefit is modest with an around 5% improvement at 5 years. Recent advance in systemic therapy has changed treatment strategy for advanced unresectable NSCLC, and also has provided a paradigm shift in treatment strategy for resectable NSCLC. For NSCLC without oncogenic driver alterations, immunotherapy using immune-checkpoint inhibitors may improve clinical outcomes in preoperative neoadjuvant setting as well as in postoperative adjuvant setting. Here, we overview recent evidence of adjuvant and neoadjuvant therapy and discuss emerging clinical questions in decision-making of treatment for potentially resectable patients with NSCLC harboring no oncogenic alterations.

Pathological complete response to neoadjuvant chemotherapy may improve antitumor immune response via reduction of regulatory T cells in muscle-invasive bladder cancer.

The prognosis for patients who achieve a pathologic complete response in bladder cancer is excellent, but the association between their prognosis and the tumor microenvironment is unclear. We investigated the tumor immune microenvironment of those with pathological complete response after platinum-based neoadjuvant chemotherapy for cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry. Our retrospective study included 12 patients with pathological complete response who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. We assessed the density of several immune cell types in pretreatment and posttreatment tissues via multiplex fluorescence immunohistochemical analysis. The median age was 67years; 10 patients were male. Nine (75%) and 3 (25%) patients were cT2 and cT3, respectively. The 5-year progression-free and overall survivals were 90% and 100%, respectively. The densities of regulatory T cells (Treg; CD3+CD4+FoxP3+ cell) were significantly decreased and almost disappeared in the tumor microenvironment of posttreatment tissue compared with pretreatment tissue. Other immune cells, such as effector T cells or M2 macrophages, were not significantly changed between posttreatment and pretreatment tissues. In pathological complete response, Tregs in the tumor immune microenvironment were significantly decreased after platinum-based chemotherapy for muscle-invasive bladder cancer. The temporary arresting of immune response in the tumor microenvironment may reflect a favorable prognosis due to the decrease of Tregs with tumor shrinkage and improve the host tumor immune response.

Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer.

In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0-1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m2. We administer at least two antiemetics, antihistamines, and sodium thiosulfate to mitigate known side effects. Postoperatively, patients are admitted to the general surgical floor, reserving the intensive care unit for those in critical condition. We follow Enhanced Recovery After Surgery principles, incorporating early ambulation and feeding into our postoperative care strategy. We have encountered encouraging results with this approach, with most patients having largely uncomplicated postoperative courses and resuming adjuvant chemotherapy within 3 to 4 weeks of surgery.

Pathological Complete Response with Platinum Containing Neoadjuvant Chemotherapy in Triple-negative Breast Cancer: An Interventional Study

Introduction: Triple-negative Breast Cancer (TNBC) accounts for 20% of all breast cancer cases globally and responds well to cytotoxic chemotherapy. The standard Neoadjuvant Chemotherapy (NAC) regimen for TNBC includes 4+4 cycles of anthracycline, cyclophosphamide, and taxane. Integrating platinum agents into the NAC has gained attention as an effective treatment for TNBC. Aim: To estimate the proportion of pathological Complete Response (pCR) in TNBC patients receiving platinum-based NAC. Materials and Methods: This interventional study enrolled 73 non metastatic TNBC patients who attended the radiotherapy Outpatient Department (OPD) of Government Medical College Thiruvananthapuram Kerala, India from April 2022 to April 2023. All patients underwent a complete history, physical examination, and tumour histopathology with Oestrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) receptor status assessment. Patients were treated with the NAC regimen: Epirubicin 90 mg/m2 , Cyclophosphamide 600 mg/m2 intravenously every three weeks for four cycles followed by Paclitaxel 175 mg/ m2 , Carboplatin according to Area Under Curve (AUC)-5 by intravenous administration every three weeks for four cycles. Clinical response was evaluated after the completion of NAC using Response Evaluation Criteria in Solid Tumours (RECIST) criteria. pCR assessment was conducted postsurgery. Study variables were entered into Microsoft Excel, and the analysis was performed using Statistical Packages for Social Sciences (SPSS) version 24.0. Results: Out of 73 patients with a mean age of 54.4 years, 33 (45.2%) patients showed complete response on clinical examination after eight cycles of Carboplatin-containing NAC, and 23 (31.5%) patients achieved pCR. Total 30 (41.1%) patients experienced complications during chemotherapy, with neutropenia and peripheral neuropathy being the most common, each occurring in 22 (30.1%) patients. Conclusion: In present study, one-third of the patients achieved pCR with platinum-based NAC with an acceptable side-effect profile. It represents a beneficial treatment option for TNBC patients; however, the impact of pCR on survival requires further validation through long-term studies. Given the poor prognosis and limited treatment options for TNBC, the addition of affordable and available agents to the existing chemotherapy regimen could potentially revolutionize the treatment of these patients.

NeoSCORE II: three vs four cycles of neoadjuvant sintilimab+chemotherapy for squamous non-small-cell lung cancer.

Immune checkpoint inhibitors (ICIs) plus chemotherapy has demonstrated efficacy in resectable non-small-cell lung cancer (NSCLC), yet the optimal period of neoadjuvant immunochemotherapy is undetermined. In a phase II study (neoSCORE, NCT04459611), more neoadjuvant therapy cycles appeared to provide greater pathological remission, and patients with squamous NSCLC had a better major pathological responserate than those with nonsquamous NSCLC. Sintilimab, a monoclonal anti-PD-1 antibody, has shown encouraging antitumor activity and safety in multiple cancers, including NSCLC. Here, we describe the study design of neoSCORE II (NCT05429463), a randomized, open-label, multicenter phase IIItrial comparing the efficacy and safety of three cycles with four cycles of neoadjuvant sintilimab plus platinum-based chemotherapy in resectable stage IIA-IIIB squamous NSCLC. Trial registration number: NCT05429463 (ClinicalTrials.gov).

3–4 Cycles versus 6 Cycles Neoadjuvant Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer: Survival Is Not Determined by the Number of Neoadjuvant Chemotherapy Cycles

Introduction: The aim of this study was to compare the disease-free survival (DFS) and overall survival (OS) of patients who underwent interval cytoreductive surgery after 3–4 cycles or 6 cycles of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer patients. Methods: Out of 219 patients with advanced epithelial ovarian cancer, 123 patients received 3–4 cycles and 96 patients received 6 cycles of platinum-based NACT. Afterward, laparotomy was performed for interval cytoreductive surgery. Results: No statistically significant difference was found for DFS and OS of the patients who received 3–4 cycles and those who received 6 cycles of NACT (HR: 1.047, 95.0% CI [0.779–1.407]; p: 0.746 for DFS, and HR: 1.181, 95.0% CI [0.818–1.707]; p: 0.368 for OS). Evaluating 123 patients who received 3–4 cycles of NACT, 87 patients (70.7%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS compared to 36 patients (29.3%) with any residual tumor (HR: 1.830, 95.0% CI [1.194–2.806]; p: 0.003 for DFS, and HR: 1.946, 95.0% CI [1.166–3.250]; p: 0.009 for OS). 96 patients who received 6 courses of NACT were evaluated; 63 patients (65.6%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS than 33 patients (34.4%) with any residual tumor (HR: 1.716, 9 5.0% CI [1.092–2.697]; p: 0.010 for DFS, and HR: 1.921, 95.0% CI [1.125–3.282]; p: 0.013 for OS). Conclusion: In patients with advanced ovarian cancer, there is no significant difference in DFS and OS between 3 and 4 cycles or 6 cycles of NACT. The most important factor determining survival is whether macroscopic residual tumor tissue remains after interval cytoreductive surgery following NACT.

Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway.

Chemoresistance is a significant barrier to effective cancer treatment. Potential mechanisms for chemoresistance include reactive oxygen species (ROS) accumulation and expression of chemoresistance-promoting genes. Here, we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance. By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer (NSCLC) and paired serum samples pre- and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy, performing immunohistochemistry (IHC) assays on 188 NSCLC tumor samples, using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) assays, as well as RNA immunoprecipitation (RIP) and RNA pull-down analyses, we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy. The expression of hemoglobin subunit beta (HBB) and NDUFAF5 significantly increases with the development of chemoresistance. LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy. LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria. Importantly, preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo. Overall, lncRNA16 is a promising therapeutic target for overcoming chemoresistance, and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.

264P Tumor-infiltrating lymphocytes (TILs) for prediction of response to platinum-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC): Final analysis

264P Tumor-infiltrating lymphocytes (TILs) for prediction of response to platinum-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC): Final analysis

268. DEVELOPMENT OF A NOVEL ESOPHAGUS-ON-A-CHIP MODEL: A HIGH-FIDELITY PLATFORM FOR DIRECTING PERSONALIZED THERAPY IN ESOPHAGEAL ADENOCARCINOMA

Abstract Background 80% of patients diagnosed with esophageal adenocarcinoma (EAC) die of disease. Current standard of care for EAC is systemic cytotoxic, platinum-based neoadjuvant chemotherapy followed by resection and additional rounds of chemotherapy. Locally advanced, resectable patients often fail to respond due to intrinsic and/or acquired chemoresistance. Traditional preclinical models fail to offer alternative salvage options. To our knowledge, this is the first high-fidelity dynamic 3D platform implemented to study esophageal function, pathophysiology, and drug effects. Methods Primary tissues obtained from EAC patients at diagnostic biopsy were propagated into patient-derived organoids (PDOs). The upper (mucosal) channel of the esophagus-chip was designated for PDO-derived epithelial cells, while the lower stromal channel was designated for matched fibroblasts. Autologous cell types were exposed to a physiologically relevant flow of nutrient media and microtissues were formed. Epithelial permeability was determined by cascade blue assay. Using this model, a clinically relevant chemotherapy protocol was administered to study patient-specific tumor response. To determine microtissue development and cellular fate in response to chemotherapy, level of several epithelial/mesenchymal biomarkers were evaluated. Results Study cohort consisted of both chemo-sensitive and -resistant EAC patients. Esophagus-chip models were developed with samples from patient-matched tumor and normal tissue. Chips recapitulated morphological and histological features of their parental tissues. Epithelial barrier integrity was established within 5 days on-chip. Scanning electron microscopy revealed the presence of pleomorphic cells and mature microvilli in EAC-chips. In vitro administration of docetaxel triplet chemotherapy demonstrated efficacy similar to that observed in the clinical setting when assessed directly or indirectly. Confocal imaging revealed treatment-associated differential expression of epithelial (CK7, CK19), and mesenchymal (vimentin) markers. Conclusion 3D-organoids conserve cellular heterogeneity of source patients, whereas esophagus-on-chip expand on this diversity by adding microphysiological relevance, stromal influence &amp; flexible complexity. This high-fidelity biomimetic platform enables clinical mimicry and can predict patient-specific chemosensitivity within a clinically relevant timeframe. This esophagus-chip system is a promising potential replacement for both inefficient preclinical animal models and existing tumor-only avatars lacking stromal and microphysiological context.

Origin of Residual Tumor Masses in BRCA1/2-Driven Ovarian Carcinomas Treated by Neoadjuvant Chemotherapy: Selection of Preexisting BRCA1/2-Proficient Tumor Cells but Not the Gain of Second ORF-Restoring Mutation

Introduction: Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response. Methods: We analyzed paired primary and residual tumor tissues from 30 patients with hereditary BRCA1/2-driven OCs (BRCA1: 17; BRCA2: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range: 3–6). BRCA1/2 and TP53 genes were analyzed by the next-generation sequencing. The ratio between TP53 mutation-specific versus wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between BRCA1/2-mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity (LOH or ROH, respectively). Results: All 30 OCs had BRCA1/2 LOH in primary tumor and carried somatic TP53 mutation. Twenty-eight OCs had sufficient tumor cell cellularity in the post-NACT tissue to evaluate the ratio between mutated and wild-type BRCA1/2 alleles. Five (18%) out of 28 informative tumor pairs showed transition from LOH to ROH during NACT presumably affecting all or the vast majority of residual tumor cells. There were no signals of the emergence of a second open reading frame-restoring BRCA1/2 mutation. Conclusion: Chemonaive BRCA1/2-driven carcinomas may contain a fraction of tumor cells with preserved BRCA1/2 heterozygosity. NACT can cause a selection of pre-existing BRCA1/2-proficient tumor cells, without gaining secondary reversal BRCA1/2 mutations.