Adjuvant Platinum-based Chemotherapy Research Articles

Minimizing overtreatment and maximizing oncologic outcomes in upper tract urothelial carcinoma

Purpose of review An update on the latest advances in the management of upper tract urothelial carcinoma (UTUC), with an emphasis on strategies to optimize oncologic outcomes while minimizing overtreatment. Recent findings Recent high-quality trials have changed the landscape of UTUC treatment. Emerging tools including 3D histology and measurement of cell free tumor DNA may improve diagnostic accuracy of disease grading and staging, and be used in monitoring treatment response. Novel therapies show promise of reducing low-grade UTUC disease recurrence at the cost of significant side-effects. Platinum-based neoadjuvant chemotherapy in high-grade/muscle-invasive disease showed complete pathological response in a subset of patients, but difficult to predict responders. Adjuvant platinum-based chemotherapy exhibited a clear survival benefit, but immunotherapy did not, suggesting possible overtreatment with these agents. Molecularly-targeted therapies in metastatic UTUC have shown the greatest recent oncologic advances, but exhibit a high adverse event-rate. Summary Low-grade UTUC has the potential for overtreatment, as it exhibits low metastatic-potential and excellent survival. For high-grade and advanced-stage UTUC, these carry high mortality rates and require more aggressive treatment, but studies are limited by inaccurate grading and staging which can lead to overtreatment especially in the neoadjuvant setting. Emerging technologies will help improve diagnostic accuracy and noninvasive monitoring of treatment response.

The biologic landscape and therapeutic implications of upper tract urothelial cancer.

Management of upper tract urothelial cancer (UTUC) has been largely extrapolated from bladder cancer due to its rarity; however, unique biological and clinical differences between UTUC and bladder cancer have been uncovered. The purpose of this review is to present the current therapeutic landscape of UTUC with an emphasis on biologically driven rationale. Prospective trials for patients with high-risk localized UTUC have shown improved outcomes with adjuvant and neoadjuvant platinum-based chemotherapy. However, the timing of therapy relative to nephroureterectomy may impact platinum eligibility due to renal functional decline following surgery. In recent years, emerging therapeutic classes including immune checkpoint inhibition, antibody drug conjugates, and targeted therapies have emerged as tolerable alternatives to platinum-based chemotherapy in treating metastatic disease. Biomarker-selected therapies, including those targeting HER2 and FGFR3, have shown encouraging results and are relevant to UTUC based on increased expressions of these targets; however, no prospective study to date has been powered to assess the effect of these modern treatments on patients with UTUC specifically. Unique biological insights into UTUC pathogenesis and risk factors have expanded the therapeutic landscape for these patients beyond conventional platinum-based chemotherapeutic approaches. Novel therapeutic classes have emerged to guide more precise approaches in treating patients with urothelial cancer, with a need for further trials powered specifically to the UTUC population.

Prognostic impact of interstitial lung disease on pulmonary high-grade neuroendocrine carcinoma

Pulmonary high-grade neuroendocrine carcinomas (HGNECs) have poor prognoses and require multimodal treatment, and interstitial lung disease (ILD) restricts sufficient treatment of patients with lung cancer. We aimed to clarify ILD’s prognostic impact on pulmonary HGNEC, which has previously gone unreported. We retrospectively analyzed 53 patients with HGNEC who underwent resections at our department between 2006 and 2021 and evaluated the clinicopathological prognostic features, including ILD. The patients’ mean age was 70 years; 46 (87%) were male, and all were smokers. Large-cell neuroendocrine and small-cell lung carcinomas were diagnosed in 36 (68%) and 17 (32%) patients, respectively. The pathological stages were stage I, II, and III in 31 (58%), 11 (21%), and 11 (21%) patients, respectively. Nine patients (17%) had ILD, which was a significant overall survival prognostic factor in a multivariate Cox proportional hazards regression analysis (p = 0.048), along with lymph node metastasis (p = 0.004) and non-administration of platinum-based adjuvant chemotherapy (p = 0.003). The 5 year survival rate of the ILD patients was 0%, significantly worse than that of patients without ILD (58.7%; p = 0.003). Patients with HGNEC and ILD had a poor prognosis owing to adjuvant therapy’s limited availability for recurrence and the development of acute exacerbations associated with ILD.

Omission of lymphadenectomy in patients with advanced epithelial ovarian cancer treated with primary or interval cytoreductive surgery after neoadjuvant chemotherapy: The CARACO phase III randomized trial.

LBA5505 Background: Lion trial demonstrated the lack of benefit of retroperitoneal pelvic and paraaortic lymphadenectomy (RPPL) in primary surgery in advanced epithelial ovarian cancer (AEOC) with clinically negative lymph nodes. As a consequence, the question of RPPL during interval cytoreductive surgery after neoadjuvant chemotherapy remains open. Methods: CARACO was a prospective multi-institutional phase III trial including patients with newly diagnosed AEOC FIGO III-IV, with no pre- and intra-operative suspicious lymph nodes, randomized intra-operatively to RPPL versus no-RPPL, stratified by surgical strategy (primary surgery, surgery after neoadjuvant chemotherapy). The primary endpoint was progression free survival (PFS). The target sample size was 450 evaluable patients, providing 80% power at 5% alpha based on the hypothesis of a 5 years PFS of 41%. Results: Between December 2008 and March 2020, 379 patients were randomly assigned to RPPL (n=181) or no-RPPL (n=187), 11 patients were excluded. Our required sample size was not reached because of a stop of inclusion after the publication of the Lion trial. The median number of removed lymph nodes in patients randomized to RPPL was 27 [IQR=19-36]. 75% of the patients were treated with neoadjuvant chemotherapy (244 patients treated with 3 or 4 cycles before interval surgery and 41 patients treated with 6 cycles before delayed surgery) and 83 patients treated with primary surgery followed with adjuvant platinum-based chemotherapy. The rate of surgery with no residual was 86% and 88% respectively in the No RPPL and the RPPL arm. Lymph node metastases were diagnosed in 49% of the patients in the RPPL arm, with a median of 3 involved lymph nodes [IQR=2-7]. After a median follow up of 9 years, median PFS in the no-RPPL arm and in the RPPL arm was 14.8 months and 18.5 months respectively (HR 0.98, 95%CI 0.78-1.22, p=0.86). Median OS was not significantly different: 48.9 months and 58.0 months in the No RPPL and RPPL arm respectively (HR 0.96, 95%CI 0.75-1.22 p=0.72). Results considering progression free and overall survival were not different in the subgroup of patients with a complete surgery or a neoadjuvant chemotherapy. Serious post-operative complications occurred more frequently in the RPPL arm: re-laparotomies 8.3% vs 3.2% [p=0.03], transfusion rate (34% vs 25%, p=0.05). Mortality within 60 days after surgery was similar between arms (1.1 vs 0.5% [p=0.54]) respectively. Conclusions: CARACO trial is the first randomized trial showing that systematic lymphadenectomy should be omitted in AEOC with clinically negative lymph nodes also in patients undergoing neoadjuvant chemotherapy and interval complete surgery. This surgical de-escalation allows to significantly reduce serious post operative morbidity. Clinical trial information: NCT01218490 .

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

Adjuvant icotinib of 12 months or 6 months versus observation following adjuvant chemotherapy for resected EGFR-mutated stage II–IIIA non-small-cell lung cancer (ICTAN, GASTO1002): A randomized phase 3 trial.

8004 Background: The efficacy, safety and ideal treatment duration of adjuvant icotinib (first-generation EGFR tyrosine kinase inhibitor) for patients with completely resected EGFR-mutated non-small-cell lung cancer (NSCLC) after adjuvant chemotherapy were not known in 2014, when this study was initiated. This phase 3 trial investigated whether icotinib following adjuvant chemotherapy improves clinical outcomes compared with observation in stage II-IIIA NSCLC harboring EGFR mutation. Methods: This is a multicenter, randomized, open-label, phase 3 trial. From July 2014 to December 2021, patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after platinum-based adjuvant chemotherapy were enrolled. Patients were assigned in a 1:1:1 ratio to receive icotinib (125mg, three times daily) for 12 months, icotinib for 6 months or to observation. The primary endpoint was disease-free survival (DFS) in the intention-to-treat population. Results: This trial was terminated early due to slow accrual.A total of 251 patients were randomized, with 84 patients in the 12-month icotinib group, 84 patients in the 6-month icotinib group, and 83 patients in the observation group. Baseline characteristics were balanced between the groups. After a median follow-up of 61.4 months, 6 months of icotinib significantly improved DFS (HR: 0.41, 95% CI, 0.27-0.62; P = 0.000025) and overall survival (OS, HR: 0.56, 95% CI, 0.32-0.98; P = 0.041) compared with observation. Adjuvant icotinib of 12 months also significantly improved DFS (HR: 0.40, 95% CI, 0.27-0.61; P = 0.000014) and OS (HR: 0.55, 95% CI, 0.32-0.96; P = 0.035) compared with observation. Adjuvant icotinib of 12 months did not improve DFS (HR: 0.97; P = 0.89) and OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Median DFS was 61.8 months (95% CI, 43.3 to 80.3) for the 12-month icotinib group, 63.2 months (95% CI, 44.8 to 81.6) for the 6-month icotinib group compared with 23.7 months (95% CI, 16.5 to 30.9) for the observation group. The 5-year DFS and OS for the 12-month icotinib, 6-month icotinib and observation groups were 51.3%, 50.1% and 24.8%; and 74.5%, 74.0% and 65.1%; respectively. No differences in efficacy pertaining to icotinib duration were found in any of the subgroups. Rates of adverse events of grade 3 or higher were 8.3%, 5.9% and 2.4% for the 12-month icotinib, 6-month icotinib and observation groups, respectively. The safety profile remained similar to the previous reports for icotinib. Conclusions: Adjuvant icotinib for 12 months and 6 months provide a significant DFS and OS benefit compared with observation in patients with completely resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile. Nevertheless, 12 months of icotinib had no additional benefit compared with 6 months. Clinical trial information: NCT01996098 .

Adjuvant immunotherapy and targeted therapy in early and locally advanced resectable lung cancer: expanding treatment tentacles?

Adjuvant platinum-based chemotherapy has been the main treatment following surgical resection with curative intent in early and locally advanced nonsmall cell lung cancer (NSCLC) albeit with a 5% improvement in 5-year survival rates. Recent advances in biomarkers pave the way for targeted treatments and immunotherapy in a broader spectrum of patients with subsequently improved clinical outcomes. Targeted treatments and immunotherapy have established their place in the adjuvant setting of resected NSCLC.

Stage I and II nonsmall cell lung cancer treatment options.

Chest radiography, computed tomography (CT) and positron emission tomography (PET)-CT are required for staging nonsmall cell lung cancers. Stage I cancers may be up to 4 cm in maximal diameter, with stage IA tumours being up to 3 cm and stage IB up to 4 cm. A lung cancer becomes stage II if the tumour is between 4 and ≤5 cm (stage IIA), or it spreads to ipsilateral peribronchial or hilar lymph nodes (stage IIB). Stage IA tumours should be surgically resected, ideally using minimally invasive methods. Lobectomy is usually performed, although some studies have shown good outcomes for sublobar resections. If surgery is not possible, stereotactic body radiotherapy is a good alternative. This involves delivering a few high-dose radiation treatments at very high precision. For stage IB to IIB disease, combinations of surgery, chemotherapy or immunotherapy and radiotherapy are used. There is evidence that neoadjuvant treatment (immunotherapy with nivolumab and chemotherapy for stage IB and II) optimises outcomes. Adjuvant chemotherapy with a platinum-based doublet (typically cisplatin+vinorelbine) should be offered for resected stage IIB tumours and considered for resected IIA tumours. Adjuvant pembrolizumab is used for stage IB-IIIA following resection and adjuvant platinum-based chemotherapy. Osimertinib may be used for resected stage IB to IIIA cancers which have relevant mutations (epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution). There are no fixed guidelines for follow-up, but most centres recommend 6-monthly CT scanning for the first 2-3 years after definitive treatment, followed by annual scans.

Rationale and study design of the KOV-HIPEC-04: A phase III randomized controlled trial in primary stage III and IV ovarian cancer after interval cytoreductive surgery (FOCUS).

TPS5636 Background: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) during interval cytoreductive surgery increases progression-free and overall survival for patients with stage III ovarian cancer in two randomized controlled trials (OV-HIPEC-01 and KOV-HIPEC-01) in the era of platinum. The aim of this trial is to identify the survival benefit of HIPEC in stage III & IV ovarian cancer with maintenance therapy of bevacizumab and/or PARP inhibitor. Methods: The KOV-HIPEC-04 trial is the international, multicenter, 1:1 randomized, phase III trial that will enroll 520 patients with stage III & IV ovarian cancer who received neoadjuvant chemotherapy. Patients with residual tumor < 2.5mm after interval cytoreductive surgery will be randomized to the trial arm (HIPEC, 41.0-42.0°C cisplatin 75mg/m2, 90 minutes) or control arm. After recovery from surgery, patients will receive postoperative platinum-based adjuvant chemotherapy followed by maintenance therapy with PARP inhibitor or bevacizumab by the institutional guideline based on BRCA/HRD status. The primary endpoint is to evaluate overall survival (OS); secondary objectives are progression-free survival (PFS), cancer-specific survival, time to the first subsequent therapy, safety, and quality of life. Assuming that the enrollment period is 5 years and the follow-up period is 3 years, the total number of events required is 263. Based on the log-rank test, the total number of subjects required to prove HR 0.67 with a two-sided alpha of 0.05 and 90% power is 494. Considering 5% drop-out, 520 patients are finally enrolled. ClinicalTrials.gov (NCT05827523). Clinical trial information: NCT05827523 .

Testing the external validity of the POUT III trial (adjuvant platnium-based chemotherapy in upper tract urothelial carcinoma) in a North American cohort

ObjectiveThe European POUT III randomized controlled trial provided level-one evidence that adjuvant platinum-based chemotherapy is the standard of care following nephroureterectomy (RNU) for locally invasive or node-positive upper tract urothelial carcinoma. We aim to assess this European randomized controlled trial's generalizability (external validity) to a North American cohort, using a nationwide database. Materials and MethodsTo compare trial patients with those seen in real-world practice, we simulated the trial inclusion criteria using data from the National Cancer Database (NCDB). We identified patients with histologically confirmed transitional cell carcinoma who underwent RNU. The available demographic characteristics of the NCDB cohort were compared with the POUT III trial cohort using Chi-squared test. ResultsThe NCDB cohort (n = 3,380) had a significantly higher proportion of older patients (age ≥ 80: 23.5% vs. 5%), and more males (68% vs. 56.2%) than the POUT cohort (Table 1, both p < 0.001). Additionally, the rate of advanced nodal disease was higher in the NCDB (N1 9.6%, N2 9.3%) than in the POUT (N1 6%, N2 3%) cohort (p < 0.001). A more extensive lymph node dissection was performed in NCDB vs. POUT patients (node≥10 10.9% vs. 3%, p < 0.001). Sensitivity analysis removing all subjects with a Charlson Comorbidity Index > 0 did not change the significance of any results. ConclusionsWhile the primary disease stage was similar, the rate of advanced nodal disease was significantly higher in NCDB, which might be explained partially by the more extensive lymph node dissection performed in the latter. These differences warrant caution when applying the POUT III findings to North American patients.

Fulminant myocarditis during postoperative adjuvant chemotherapy for lung cancer with atezolizumab: a case report

BackgroundPostoperative adjuvant systemic therapy with atezolizumab for lung cancer has been reported to be effective. Although myocarditis is a rare immune adverse event associated with atezolizumab, it can have a serious course and should be treated with caution. We herein report a case of fulminant myocarditis during adjuvant systemic therapy with atezolizumab.Case presentationThe patient was a 49-year-old Asian woman. She was diagnosed with pT2aN1M0 stage IIB (Programmed Death Ligand 1(PD-L1), 50%) after surgery for right upper lobe lung adenocarcinoma. Atezolizumab was administered following platinum-based adjuvant chemotherapy. On day 14, the patient was hospitalized because of deterioration in her general condition caused by fever. On day 16, she developed dyspnea, which worsened, and on day 17, she experienced shock. Blood tests, echocardiography, and cardiac catheterization were performed, and the patient was diagnosed with cardiogenic shock due to myocarditis. Initial measures did not improve the patient’s shock state. The patient was transferred to hospital for the use of an assistive circulatory system. Pulse steroid therapy was administered, and myocarditis showed a tendency toward improvement. A retrospective review of the patient’s history revealed a decreased lymphocyte count and an increase in the neutrophil/lymphocyte ratio, which may be useful for detecting severe immune-related adverse events. The troponin levels were elevated, but creatine phosphokinase level remained within the normal range.ConclusionMyocarditis can be fatal due to the rapid progression of symptoms. Close follow-up, a prompt diagnosis, and therapeutic intervention are important. Decreased lymphocyte counts, increased neutrophil/lymphocyte ratios, and the measurement of multiple myocardial biomarkers are considered useful for the early diagnosis of myocarditis.

Impact of platinum-based chemotherapy on the tumor mutational burden and immune microenvironment in non-small cell lung cancer with postoperative recurrence.

To investigate the impact of platinum-based adjuvant chemotherapy on the immunotherapeutic biomarkersof postoperative recurrent tumors in non-small cell lung cancer (NSCLC). This study involved twenty-two cases of NSCLC, all of which underwent postoperative platinum-based chemotherapy, with matched surgical samples obtained from both their primary tumors (PTs) and recurrent tumors (RTs). Multiplex immunofluorescence was performed to assess the tumor proportion score (TPS) and immune cells (IC) on whole sections. Whole exon sequencing (WES) was conducted to investigate the tumor mutational burden (TMB) and tumor neoantigen burden (TNB). Compared to paired PTs, RTs exhibited higher PD-L1 expression, along with a slightly elevated density of intratumoral PD-L1+ cells (p = 0.082) and an increased tumor proportion score (mean TPS: 40.51% vs. 28.56%, p = 0.046). Regarding IC infiltration, RTs generally demonstrated significantly lower CD8+ cytotoxic T lymphocyte (CTL) density (p = 0.011) and lower CD68+ macrophage density (p = 0.005), with a loss of tertiary lymphoid structure (TLS). The comparison between RTs and PTs revealed no significant differences in TMB (p = 0.795), whereas the count of TNB in RTs was notably increased compared to PTs (p = 0.033). Prognosis analysis indicated that a higher density of CD8+ CTLs in RTs was positively correlated with improved overall survival (OS). In NSCLC patients with a history of postoperative platinum-based chemotherapy, the RTs demonstrated a trend towards increased PD-L1 expression and TMB/TNB, but a state of immunosuppression characterized by decreased ICs and loss of TLS, which may potentially impact the therapeutic benefits of immunotherapy.

Characteristics of patients (pts) with muscle-invasive urothelial carcinoma (MIUC) who received adjuvant nivolumab (NIVO) or adjuvant platinum-based chemotherapy (CHEMO) in the real-world (RW) setting.

Characteristics of patients (pts) with muscle-invasive urothelial carcinoma (MIUC) who received adjuvant nivolumab (NIVO) or adjuvant platinum-based chemotherapy (CHEMO) in the real-world (RW) setting.

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.

Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer.

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.

Abstract B027: Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer

Abstract Purpose: Ovarian cancer is the leading cause of death among cancers of the female reproductive system. Surgery and platinum-based adjuvant chemotherapy followed by PARP inhibitor (PARPi) maintenance therapy is standard treatment for most patients diagnosed with ovarian cancer. The mechanism of action of PARPi and platinum-based therapy involves the induction of DNA damage, which requires the Fanconi Anemia (FA)- BRCA pathway for repair, making these agents most beneficial in cancers with BRCA mutations. However, 75% of patients with ovarian cancer have BRCA wild type tumors and therefore their benefit from PARPi is limited. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recent research demonstrated TTFields induce a state of BRCAness in multiple cancer types, as well as anticancer effects in ovarian cancer preclinical models. This study investigated the impact of TTFields concomitant with carboplatin or PARPi in ovarian cancer cell lines. Methods: A2780 (BRCA wild type), OVCAR3 (BRCA mutated), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or concomitant with application of carboplatin or a PARPi (olaparib or niraparib). Efficacy assessments included cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying the effects on cell count and colony formation. Results: TTFields treatment reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib exhibited dose-dependent effects in all cell lines. When TTFields were applied together with these drugs, a synergistic interaction was observed in the BRCA wild-type A2780 cells and platinum-resistant A2780cis cells, while an additive effect was noted in the BRCA mutant OVCAR-3 cells. Conclusions: This data implies potential advantages for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even without underlying BRCA mutations. This aligns with the BRCAness state induced by TTFields and suggests a benefit in platinum resistant cancer. Overall, TTFields may augment the efficacy of ovarian cancer treatment in both adjuvant and maintenance settings. Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B027.

Effect of tumor type on response to adjuvant platinum-based chemotherapy and prognosis in patients with stage II-IV epithelial ovarian carcinoma.

To evaluate the effect of histological subtype on oncological outcome and adjuvant platinum-based chemotherapy response in patients with epithelial ovarian cancer (EOC). The study group was created with stage II-IV EOC patients. Progression-free survival (PFS) and disease-specific survival (DSS) estimates were determined by using the Kaplan-Meier method. The log-rank test and cox proportional hazards model were performed. A total 396 patients were included the study. Tumor type was serous in 332 (83.8%). Two hundred and thirty-one patients (58.3%) had maximal cytoreduction. Three hundred and twenty-seven (82.6%) patients received complete clinical response. Refractory disease was present in 69 (17.4%) patients. In patients with complete clinical response, 183 (56%) patients recurred. Five-year PFS was 32% in serous group and 31% in non-serous group (p = 0.755). Five-year DSS was 78% in serous group and 87% in non-serous group (p = 0.084). On multivariate analysis, recurrence rates 1.959 times (95% CI: 1.224-3.085; p = 0.004), death rates 2.624 times (95% CI: 1.328-5.185; p = 0.005) higher in patients with optimal cytoreduction than patients with maximal cytoreduction, respectively. Although the rate of maximal cytoreduction was higher in patients with non-serous tumor type, the rate of refractory disease was higher after adjuvant chemotherapy. However, the recurrence rate was higher in serous tumor type. Survival rates were similar in serous and non-serous tumor types. Maximal cytoreduction was an independent predictor factor for survival. Maximal cytoreduction should be the main target in EOC.

Personalized adjuvant chemotherapy for stage II–III non-small cell lung cancer

Surgery is the standard of care for non-small cell lung cancer (NSCLC). The overall survival rates especially in patients with locally advanced lung cancer are low. The resistance of cancer cells to chemotherapeutic drugs reduces the efficacy of treatment. Special attention is paid to the feasibility of assessing the tumor sensitivity to certain chemotherapy drugs. Currently, the most studied predictors are monoresistance and multidrug resistance genes, such as ABCC5, RRM1, ERCC1, BRCA1, TOP1, TOP2a, TUBB3 and TYMS.The aim of the study was to analyze the outcomes of combined modality treatment using radical surgery and personalized adjuvant chemotherapy for stage II–III NSCLC.Material and Methods. The study included 120 patients with stage II–III NSCLC, who underwent radical lung resection with mediastinal ipsilateral lymph node dissection. The patients were then divided into two groups. The main group consisted of 60 patients who received personalized platinum-based adjuvant chemotherapy based on the expression levels of the genes, such as ABCC5, RRM1, ERCC1, BRCA1, TOP1, TOP2a, TUBB3 and TYMS. The control group consisted of 60 patients who received postoperative chemotherapy empirically.Results. In the main group, disease progression occurred in 14 out of 60 patients, three-year disease-free survival (DFS) was 76.7 % (the median was not reached). In the control group, DFS was 53.3 % (28 out of 60 patients), the median was 31.0 (4–36 months); the differences were statistically significant: Logrank test χ2 =4.382 p=0.036. The overall three–year survival rate was 90.0 % in the main group (6/60 patients died) and 61.7 % in the control group (23/60 patients died), the differences were statistically signifcant: Logrank test χ2 =6.915, p=0.009.Conclusion. The personalized adjuvant chemotherapy resulted in the improved three-year relapse-free and overall survival rates in NSCLC patients.

Prognostic Significance of Tumor Mutation Burden among Patients with Non-small Cell Lung Cancer Who Received Platinum-based Adjuvant Chemotherapy: An Exploratory Study.

This study aimed to investigate the prognostic significance of tumor mutation burden (TMB) among patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Tumor tissue specimens after surgical resection were collected for DNA extraction. Somatic mutation detection and TMB analysis were conducted using next-generation sequencing (NGS). Recurrence status of the patients was assessed in the hospital during the adjuvant chemotherapy period, and long-term survival data of patients were obtained by telephone follow-up. Univariate analysis between TMB status and prognosis was carried out by survival analysis. A retrospective review of 78 patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy showed a median disease-free survival of 3.6 years and median overall survival (OS) of 5.3 years. NGS analysis exhibited that the most common mutated somatic genes among the 78 patients were tumor suppressor protein p53 (TP53), epidermal growth factor receptor, low-density lipoprotein receptor related protein 1B, DNA methyltransferase 3 alpha and FAT atypical cadherin 3, and their prevalence was 56.4%, 48.7%, 37.2%, 30.7%, and 25.6%, respectively. TMB status was divided into TMB-L (≤ 4.5/Mb) and TMB-H (> 4.5/Mb) based on the median TMB threshold. Relevance of TMB to prognosis suggested that the median OS of patients with TMB-L was significantly longer than that of patients with TMB-H (NR vs. 4.6, P = 0.014). Higher TMB status conferred a worse implication on OS among patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy.

Overview of Lung Cancer

The two main types of lung cancer are small cell carcinoma and non-small cell carcinoma. Lung cancer is a primary bronchogenic carcinoma. Patients who are diagnosed with lung cancer typically exhibit symptoms like hemoptysis, dyspnea, chronic cough, chest pain, or weight loss. Since the onset of symptoms typically indicates that a patient's stage has already progressed, screening with low-dose chest CT (LDCT) exams is advised for high-risk patients. Cytology and core biopsy specimens are the main sources of the diagnosis for these patients. Staging, histology, genetic, and immunotherapy biomarker tests form the basis of the treatment. The most often used pharmacological therapies include radiotherapy, adjuvant platinum-based chemotherapy, surgery, which might involve mediastinal lymph node dissection or lymph node sampling, as well as total removal of the tumor (typically stages I and II). Currently, meanwhile, immunotherapy is the most advanced form of treatment for NSCLC that is oncogenic driver negative