TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A risk score based on polyamine metabolism and chemotherapy-related genes predicts prognosis and immune cells infiltration of lung adenocarcinoma.

We aimed to explore whether the genes associated with both platinum-based therapy and polyamine metabolism could predict the prognosis of LUAD. We searched for the differential expression genes (DEGs) associated with platinum-based therapy, then we interacted them with polyamine metabolism-related genes to obtain hub genes. Subsequently, we analysed the main immune cell populations in LUAD using the scRNA-seq data, and evaluated the activity of polyamine metabolism of different cell subpopulations. The DEGs between high and low activity groups were screened to identify key DEGs to establish prognostic risk score model. We further elucidated the landscape of immune cells, mutation and drug sensitivity analysis in different risk groups. Finally, we got 10 hub genes associated with both platinum-based chemotherapy and polyamine metabolism, and found that these hub genes mainly affected signalling transduction pathways. B cells and mast cells with highest polyamine metabolism activity, while NK cells were found with lowest polyamine metabolism activity based on scRNA-seq data. DEGs between high and low polyamine metabolism activity groups were identified, then 6 key genes were screened out to build risk score, which showed a good predictive power. The risk score showed a universal negative correlation with immunotherapy checkpoint genes and the cytotoxic T cells infiltration. The mutation rates of EGFR in low-risk group was significantly higher than that of high-risk group. In conclusion, we developed a risk score based on key genes associated with platinum-based therapy and polyamine metabolism, which provide a new perspective for prognosis prediction of LUAD.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

BRCA1/2 reversion mutations in a pan-cancer cohort.

Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events-BRCA1 (n = 3), BRCA2 (n = 18)-including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion-insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

REV7 is involved in outcomes of platinum-based chemotherapy in pancreatic cancer by controlling the DNA damage response.

REV7 is a multifunctional protein implicated in various biological processes, including DNA damage response. REV7 expression in human cancer cells affects their sensitivity to DNA-damaging agents. In the present study, we investigated the significance of REV7 in pancreatic ductal adenocarcinoma (PDAC). REV7 expression was immunohistochemically examined in 92 resected PDAC specimens and 60 endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens of unresectable PDAC treated with platinum-based chemotherapy, and its association with clinicopathologic features was analyzed. Although REV7 expression was not significantly associated with the progression of primary tumors (T-factor and Stage) in either resected or unresectable PDAC, decreased levels of REV7 expression in EUS-FNAB specimens of unresectable PDAC were significantly associated with better outcomes of platinum-based chemotherapy and a favorable prognosis. REV7-deficient PDAC cell lines showed suppressed cell growth and enhanced sensitivity to cisplatin in vitro. Tumor-bearing mice generated using REV7-deficient PDAC cell lines also showed enhanced sensitivity to cisplatin in vivo. RNA sequencing analysis using WT and REV7-deficient PDAC cell lines revealed that REV7 inactivation promoted the downregulation of genes involved in the DNA repair and the upregulation of genes involved in apoptosis. Our results indicate that decreased expression of REV7 is associated with better outcomes of platinum-based chemotherapy in PDAC by suppressing the DNA damage response. It is also suggested that REV7 is a useful biomarker for predicting the outcome of platinum-based chemotherapy and the prognosis of unresectable PDAC and is a potential target for PDAC treatment.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Adjunctive Surgery Is Often Without Oncological Benefit at Time of Postchemotherapy Retroperitoneal Lymph Node Dissection.

PURPOSE: Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminomatous germ cell tumors (GCTs) aims to resect all remaining metastatic tissue. Resection of adjacent visceral or vascular organs is commonly performed for complete resection. Resection of organs harboring only necrosis results in relevant overtreatment. The study aimed to describe the frequency of metastatic involvement of resected organs with teratoma or viable cancer and to analyze perioperative complications and relapse-free survival. MATERIALS AND METHODS: In a 2-center study, we reviewed a cohort of 1204 patients who underwent PC-RPLND between 2008 and 2021 and identified 242 (20%) cases of adjunctive surgery during PC-RPLND. We analyzed the removed adjacent structures and the pathohistological presence of GCT elements in the resected organs: viable GCT, teratoma, or necrosis/fibrosis. Surgery-associated complications were reported according to the Clavien-Dindo classification. RESULTS: Viable GCT, teratoma, and necrosis were present in 54 (22%), 94 (39%), and 94 (39%), respectively, of all patients with adjunctive resection of adjacent organs. Vascular resections or reconstructions (n = 112; viable: 23%, teratoma: 41%, necrosis: 36%) were performed most frequently, followed by nephrectomies (n = 77; viable: 29%, teratoma: 39%, necrosis: 33%). Perioperative complications of grade ≥ IIIa occurred in 6.6% of all patients, with no difference between the viable GCT and teratoma/necrosis groups (P = .1). A total of 76 patients have been followed without a relapse for at least 36 months. Median follow-up of the whole cohort was 22 months (quartile 7 and 48). Patients with viable GCT/teratoma in the resected specimens had a significantly increased risk of recurrence by 5 years compared to patients with only necrosis (19% vs 59% vs 81%, P < .001). CONCLUSIONS: This study shows that 33% to 40% of all resections of adjacent organs do not harbor teratoma or viable GCT. This highlights the need for better patient selection for these complex patients.

Efficacy and Safety of First-Line Platinum-Based Doublet Chemotherapy in Advanced Primary Pulmonary Salivary Gland Tumors (PSGTs).

Primary pulmonary salivary gland tumors (PSGT) constitute a rare subtype of non-small cell lung cancer (NSCLC). Currently, no established treatment guidelines exist for advanced PSGT. The efficacy of platinum-based chemotherapy for PSGT within the context of NSCLC remains uncertain. Therefore, we retrospectively collected 37 PSGT patients who underwent first-line platinum-based chemotherapy from 2010 to 2023. Survival analysis, employing the Kaplan-Meier method, and group comparisons via the log rank test were conducted. Our results show that first-line platinum-based chemotherapy demonstrates favorable efficacy and manageable safety in advanced PSGT, with the combination of Paclitaxel + Platinum emerging as a preferred option.

Prognostic Value of the Geriatric Nutritional Risk Index in Previously Untreated Patients with Advanced Non-Small Cell Lung Cancer Treated with a Combination Therapy of Anti-PD-1/-PD-L1 Antibodies and Platinum-Based Chemotherapy: A Multicenter Retrospective Study.

INTRODUCTION: Combination therapy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies and platinum-based chemotherapy has been widely used as a first-line treatment for patients with unresectable advanced non-small cell lung cancer (NSCLC) in clinical settings; however, prognostic biomarkers associated with survival outcomes have not been sufficiently investigated. METHODS: We enrolled 147 previously untreated patients with advanced NSCLC who were treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy at eight institutions in Nagano Prefecture between December 2018 and April 2023. We evaluated the prognostic value of the geriatric nutritional risk index (GNRI), a systemic inflammatory nutritional biomarker calculated from body weight and serum albumin level, for patients with NSCLC treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy. RESULTS: The cutoff value of the GNRI was set at 92. The high GNRI and low GNRI groups included 88 and 59 patients, respectively. The median follow-up period was 15.9 months. The overall survival (OS) in the high GNRI group was significantly longer than that in the low GNRI group (27.9 vs. 15.6 months, p = 0.015). Multivariate analysis revealed that a high GNRI was an independently favorable prognostic predictor for OS (hazard ratio, 1.73; 95% confidence interval, 1.06-2.86; p = 0.031). CONCLUSION: The present study demonstrates that the GNRI is a useful prognostic predictor in patients with NSCLC treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy in clinical settings.

Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience.

Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0-1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies.

Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy.

BACKGROUND: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. METHODS: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. RESULTS: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. CONCLUSIONS: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.

Genetic polymorphisms as potential pharmacogenetic biomarkers for platinum-based chemotherapy in non-small cell lung cancer.

Platinum-based chemotherapy (PBC) is a widely used treatment for various solid tumors, including non-small cell lung cancer (NSCLC). However, its efficacy is often compromised by the emergence of drug resistance in patients. There is growing evidence that genetic variations may influence the susceptibility of NSCLC patients to develop resistance to PBC. Here, we provide a comprehensive overview of the mechanisms underlying platinum drug resistance and highlight the important role that genetic polymorphisms play in this process. This paper discussed the genetic variants that regulate DNA repair, cellular movement, drug transport, metabolic processing, and immune response, with a focus on their effects on response to PBC. The potential applications of these genetic polymorphisms as predictive indicators in clinical practice are explored, as are the challenges associated with their implementation.

Re-administration of platinum-based chemotherapy for recurrent endometrial cancer: an ancillary analysis of the SGSG-012/GOTIC-004/Intergroup study.

BACKGROUND: We previously demonstrated the applicability of the concept of "platinum sensitivity" in recurrent endometrial cancer. Although immune checkpoint inhibitors have been widely incorporated into endometrial cancer treatment, the debate continues regarding treatment options in patients with recurrent endometrial cancer who have previously received platinum-based chemotherapy. In this study, we assessed the duration of response to secondary platinum-based treatment using pooled data from the SGSG-012/GOTIC-004/Intergroup study. METHODS: Among the 279 participants in the SGSG-012/GOTIC-004/Intergroup study wherein platinum-based chemotherapy was re-administered for managing recurrent endometrial cancer between January 2005 and December 2009, 130 (47%) responded to chemotherapy. We compared the relationship between platinum-free interval and duration of secondary platinum-based treatment using pooled data. RESULTS: In 40 patients (31%), the duration of response to secondary platinum-based treatment exceeded the platinum-free interval. The duration of response to secondary platinum-based treatment exceeded 12 months in 51 patients (39%) [platinum-free interval: < 12 months, 14/48 (29%); 12-23 months, 18/43 (42%); 24-35 months, 8/19 (42%); ≥ 36 months, 11/20 (55%)]. In particular, in eight patients (6%), the duration of response to secondary platinum-based treatment exceeded 36 months [platinum-free interval: < 12 months, 3/48 (6%); 12-23 months, 0/19 (0%); 24-35 months, 2/19 (11%); ≥ 36 months, 3/20 (15%)]. CONCLUSIONS: Re-administration of platinum-based chemotherapy for recurrent endometrial cancer may result in a long-term response exceeding the platinum-free interval in some patients. Even in the current situation, where immune checkpoint inhibitors have been introduced, re-administration of platinum-based chemotherapy is worth considering.

Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study.

BACKGROUND: Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. METHODS: This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. RESULTS: The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. CONCLUSION: This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

BACKGROUND: ABC transporters are membrane proteins expressed in the lungs and are crucial for efflux of various chemotherapeutic agents. Polymorphisms of ABC transporters have a certain impact on the transporter activity because their expression levels may influence the extent and longevity of chemotherapeutic drug outflow, affecting patient outcomes. The present study aimed to assess the impact of ABCB1, ABCC1/2, and ABCG2 gene variants in predicting prognosis and clinical outcomes in lung carcinoma patients. METHODS: In total, 502 lung cancer patients undergoing platinum-based chemotherapy were recruited in this prospective study. Genotyping of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A), ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms in Northern Indian lung carcinoma patients were evaluated using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Poor survival outcomes were noted in patients carrying a heterozygous genotype (CT) for the ABCB1 C1236 T polymorphism compared to the wild-type genotype (CC) (p = 0.04). The mutant genotype (AA) for ABCC1 G3173 A exhibited a lower median survival time compared to the reference genotype (GG) (p = 0.009). Lower survival was observed in individuals carrying a heterozygous genotype (GA) for ABCC2 G4544 A polymorphism compared to the wild-type genotype (GG) (p = 0.017). Small cell lung cancer patients with the ABCB1 G2677 A polymorphism having a heterozygous genotype (GA) showed poor survival compared to the wild-type genotype (GG) (p = 0.03). For ABCC1 G3173 A, adenocarcinoma patients having a mutant genotype (AA) had reduced survival compared to the wild-type (GG) genotype (p = 0.03). For ABCB1 C3435 T, individuals carrying a heterozygous (CT) (p = 0.018) and mutant (TT) genotype (p = 0.007) had poor survival compared to the wild-type (CC) genotype in patients treated with pemetrexed and cisplatin. The patients administered cisplatin and irinotecan and having mutant alleles (AA) for the ABCB1 G2677 A polymorphism showed a lower survival compared to the individuals carrying wild-type alleles (GG) (p = 0.009). CONCLUSIONS: Our findings suggest that ABCB1 C1236 T, ABCB1 C3435 T, ABCB1 G2677 A, ABCC1 G3173 A, and ABCC2 G4544 A are involved in predicting prognosis. Genotyping of the ABC polymorphism is essential for predicting prognosis in lung carcinoma patients.

Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome.

BACKGROUND: Whereas neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy remains the standard treatment for patients with muscle-invasive bladder cancer (MIBC), increasing evidence suggests that checkpoint inhibitors, either alone or in combination with chemotherapy, are effective in the (neo)adjuvant setting. The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in MIBC. METHODS: Tumor tissue of 81 patients was used, including 60 patients treated with NAC and 21 patients undergoing upfront cystectomy. Multiplex immunohistochemistry was performed to assess CD3+, CD3+CD8+, CD3+CD8-FoxP3-, CD3+FoxP3+, and CD20+ cells. Patients were classified into a favorable or unfavorable outcome group based on the development of a recurrence within a year. RESULTS: The density of intratumoral CD3+ T cells decreased following NAC in patients with a recurrence at one year, while it remained stable in patients without a recurrence (median fold change 0.6 [95CI 0.3; 1.0] versus 1.0 [95CI 0.6; 2.2]). This decrease was mainly attributable to a decrease in CD3+CD8-FoxP3- and CD3+FoxP3+ T cells and was not observed in patients with an early recurrence after upfront cystectomy. Additionally, in cystectomy tissue of patients treated with NAC, median CD3+ and CD3+CD8+ T cell densities were significantly lower in patients with versus patients without a recurrence (CD3: 261. cells/mm2 [95CI 22.4; 467.2]; CD8: 189.6 cells/mm2 [95CI 2.0;462.0]). CONCLUSION: T cell density decreases following NAC in MIBC patients with poor clinical outcome. Further research is needed to investigate whether this decrease in T cell density affects the efficacy of subsequent checkpoint inhibitors. PRéCIS: The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in patients with MIBC. We reveal a decline in intratumoral CD3+ T cell density following NAC in patients with an early recurrence.

The impact of antibiotic and proton pump inhibitor use at the time of adjuvant platinum-based chemotherapy on survival in patients with endometrial cancer.

OBJECTIVE: We sought to assess the impact of antibiotic (ABX) and proton-pump inhibitor (PPI) use on progression-free (PFS) and overall survival (OS) in patients treated with adjuvant platinum-based chemotherapy (PC) for endometrial cancer (EC). METHODS: A retrospective, single-institution cohort study of EC patients treated with ≥four cycles of adjuvant PC following surgical staging from 2014 to 2020. Demographics and clinicopathologic features, including ABX and PPI use, were compared using χ2 and Fisher's exact tests. Univariate and multivariable analyses were performed, and survival outcomes were compared using the log-rank test. RESULTS: Of 325 patients, 95 (29%) received ABX, and 80 (24.6%) received PPI. ABX were associated with decreased 3-year PFS (49.9% vs. 66%; p = 0.0237) but not 3-year OS (68.9% vs. 79.9%; p = 0.0649). ABX targeting gram-positive bacteria were associated with decreased 3-year PFS (21.2% vs. 66.0% vs. 55.4%; p = 0.0038) and 3-year OS (36.5% vs. 79.9% vs. 75.6%; p = 0.0014) compared to no ABX and other ABX, respectively. PPI use was associated with decreased 3-year PFS (46.9% vs. 66.0%; p = 0.0001) and 3-year OS (60.7% vs. 81.9%; p = 0.0041) compared to no PPI. On multivariable regression analysis controlling for confounders including stage, histology, grade, radiation, and co-morbidities, PPI use was independently associated with worse PFS (HR 1.96, 95% CI 1.25-3.08; p = 0.0041) and OS (HR 2.06, 95% CI 1.01-4.18, p = 0.04). CONCLUSION: In this retrospective cohort study, we demonstrate that PPI use is independently associated with worse PFS and OS in patients with EC treated with PC. ABX use was associated with worse PFS on univariate analysis only. There is an unmet need to understand how PPI, ABX, and, potentially, the microbiome impact the effectiveness of chemotherapy in EC patients.

Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma.

BACKGROUND: To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in epithelial ovarian carcinoma (EOC) treated with primary surgery followed by platinum-based chemotherapy. METHODS: The records of primary EOC treated between Jan 1st 2002 and Dec 31st 2016 were reviewed according to the including and excluding criteria. CIN was defined as absolute neutrophil count (ANC) after chemotherapy <2.0 × 109/L. Patients with CIN were further divided into mild and severe CIN (ANC <1.0 × 109/L), early-onset and late-onset (>3 cycles) CIN. Clinical characteristic was compared by chi-square test. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier analysis, univariate and multivariate Cox regression models. RESULTS: Among 735 EOC patients enrolled, no significant differences of the prognosis were found between patients with and without CIN, early and late CIN, mild and severe CIN. However, Kaplan-Meier curve (65 vs 42 months for CIN vs non-CIN, P = .007) and Cox regression analysis (HR 1.499, 95% CI 1.142-1.966; P = .004) both revealed that CIN was significantly related with better OS in advanced EOC patients, but not for PFS. So, subgroup analysis was further conducted and date suggested that CIN was an independent predictor of better survival in advanced EOC with suboptimal surgery (PFS: 18 vs 14 months, P = .013, HR 1.526, 95% CI 1.072-2.171, P = .019; OS: 37 vs 27 months, P = .013, HR 1.455, 95% CI 1.004-2.108; P = .048). CONCLUSIONS: CIN might be used as an independent prognostic indicator of advanced EOC, especially for those patients with suboptimal surgery.

High-intensity interval training and thromboembolic events during chemotherapy for testicular cancer: a retrospective analysis from the Body & Cancer cohort.

Background: Men with testicular cancer receiving platinum-based chemotherapy have an increased risk of thromboembolic events, with incidence rates between 8-24%. A recent trial evaluating the effect of high-intensity interval training (HIIT) prematurely closed as three out of nine participants (33%) in the intervention group developed a thromboembolic event. The purpose of this retrospective cohort study was: 1) (primary) to evaluate the incidence of thromboembolic events in men receiving chemotherapy for testicular cancer who had participated in HIIT during a 6-week exercise program (Body & Cancer) 2) to describe the feasibility of this program.Material and methods: Forty men who had participated in at least one HIIT session from February 2007 to February 2020 were included. Electronic medical records were searched for incident thromboembolic events (arterial and venous) during Body & Cancer and up to one-year post-chemotherapy. Attendance, cardiorespiratory fitness (VO2-peak), and upper and lower extremity muscular strength (1 repetition maximum (RM)) were obtained from the Body & Cancer database.Results: One participant developed a thromboembolic event during Body & Cancer. No participants developed a thromboembolic event in the follow-up period. In all, data represent 160 HIIT sessions with a median attendance of eight sessions [range 1-19]. Statistically significant increases in upper and lower extremity strength were observed (8.6 (4.2 to 13.0) and 26.0 (14.9 to 37.0) kg, respectively). No significant increase in cardiorespiratory fitness was found (0.14 (-0.03 to 0.31) l/min).Conclusion: While conclusions on the safety of HIIT cannot be drawn, data from the present study do not support previous findings cautioning avoidance of HIIT due to a possible added risk of thromboembolic events in men receiving platinum-based chemotherapy for testicular cancer. Considering the potential for positive effects on cardiovascular outcomes associated with HIIT, future studies with robust design should be performed in this population to confirm these observations.