Neoadjuvant Treatment In Patients Research Articles

Texture Analysis and Prediction of Response to Neoadjuvant Treatment in Patients with Locally Advanced Rectal Cancer

Background: The purpose of this study is to determine the relationship between the texture analysis extracted from preoperative rectal magnetic resonance (MR) studies and the response to neoadjuvant treatment. Materials and Methods: In total, 88 patients with rectal adenocarcinoma who underwent staging MR between 2017 and 2022 were retrospectively enrolled. After the completion of neoadjuvant treatment, they underwent surgical resection. The tumour regression grade (TRG) was collected. Patients with TRG 1–2 were classified as responders, while patients with TRG 3 to 5 were classified as non-responders. A texture analysis was conducted using LIFEx software (v 7.6.0), where T2-weighted MR sequences on oriented axial planes were uploaded, and a region of interest (ROI) was manually drawn on a single slice. Features with a Spearman correlation index > 0.5 have been discarded, and a LASSO feature selection has been applied. Selected features were trained using bootstrapping. Results: According to the TRG classes, 49 patients (55.8%) were considered responders, while 39 (44.2) were non-responders. Two features were associated with the responder class: GLCM_Homogeneity and Discretized Histo Entropy log 2. Regarding GLCM_Homogeneity, the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were 0.779 (95% CIs = 0.771–0.816), 86% (80–90), and 67% (60–71). Regarding Discretized Histo Entropy log 2, we found 0.775 AUC (0.700–0.801), 80% sensitivity (74–83), and 63% specificity (58–69). Combining both radiomics features the radiomics signature diagnostic accuracy increased (AUC = 0.844). Finally, the AUC of 1000 bootstraps were 0.810. Conclusions: Texture analysis can be considered an advanced tool for determining a possible correlation between pre-surgical MR data and the response to neoadjuvant therapy.

Escalation of neoadjuvant therapy in triple-negative breast cancer—balancing effectiveness and toxicities

SummaryWith the incorporation of immune checkpoint inhibitors into the neoadjuvant treatment of patients with triple-negative breast cancer, we are confronted with a new toxicity profile, while adding significant improvement in pathologic complete response rates and event-free survival.

Racial Inequities in Receiving Neoadjuvant Treatment in Patients With Pancreatic Cancer Are Associated With Worse Outcomes in Louisiana.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths. In recent years, the approach to managing this malignancy has evolved toward embracing neoadjuvant treatment (NAT), backed by studies reporting its survival benefit. This study aimed to identify factors that contribute to disparities in NAT utilization and their impact on outcomes in patients with PDAC who underwent resection in Louisiana. Data on diagnosed PDAC cases were obtained from the Louisiana Tumor Registry between 2000 and 2020. We conducted multivariable logistic regression to adjust for potential confounding factors in assessing the covariate relationships with NAT use. Multivariate Cox regression analysis was performed to determine which factors were associated with survival. Chained multiple imputation was performed on covariates with missing data in multivariable regressions. The study encompassed 2121 patients who underwent resection for PDAC. Upon controlling for potential confounding variables, Black patients were on average 5.7% less likely to receive NAT than their White counterparts (ATE = 5.7, aOR= 0.56, 95% CI = 0.40-0.80, p = 0.001). After adjustment for confounding factors, there was a significant decrease in the risk of overall death for patients who received NAT (aHR = 0.82, 95% CI = 0.71-0.94, p = 0.006). There was no significant interaction between race and NAT for the risk of death. Black patients with PDAC were less likely to receive NAT before resection in Louisiana. Overall survival improved in patients who underwent NAT. These differences were independent of insurance status and poverty zip codes, and future investigations should identify modifiable barriers to access and receipt of NAT in patients with PDAC.

Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study

The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18. Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR). A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P= 0.98). No new safety signals were identified. The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen.

Feasibility and outcomes of robotic sphincter-preserving surgery for rectal cancer after neoadjuvant treatment in patients with preexisting colostomy

BackgroundDiverting colostomy followed by neoadjuvant treatment is a treatment of choice for obstructive rectal cancer. Such patients may be treated via a robotic approach with several advantages over conventional laparoscopic surgery. Conversely, the existing stoma may interfere with the optimal trocar position and thus affect the quality of robotic surgery. Moreover, the console surgeon does not face the patient, which may endanger the stoma.MethodsPatients with rectal cancer who underwent sphincter-preserving surgery were retrospectively investigated using a robotic platform after neoadjuvant treatment at our hospital. Based on pretreatment stoma creation, patients were divided into the NS (those without a stoma) and S groups (patients with a stoma). Baseline characteristics, types of neoadjuvant treatment, short-term surgical outcomes, postoperative anorectal manometric data, and survival were compared between the groups.ResultsThe NS and S groups comprised 65 and 9 patients, respectively. Conversion to laparotomy was required in three patients in the NS group. The S group required a longer console time than the NS group (median: 367 vs. 253 min, respectively, p = 0.038); however, no difference was observed in the total operative time (p = 0.15) and blood loss (p = 0.70). Postoperative complication rates, anorectal function, and oncological outcomes were similar between the groups.ConclusionsAlthough console time was longer in patients with a stoma, robotic surgery could be performed safely like in those without a stoma after neoadjuvant treatment.

EGFR-TKI as neoadjuvant treatment in patients with NSCLC with EGFR sensitive mutation: A retrospective real-world analysis.

8081 Background: This study aimed to evaluate the efficacy and outcome of Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as preoperative neoadjuvant treatment in patients with NSCLC and EGFR sensitive mutation. Methods: A retrospective analysis was conducted. Patients with resectable stage I-III NSCLCs and received neoadjuvant treatment with any generation of EGFR-TKI before surgical resection were enrolled. The primary endpoint were major pathological response (MPR) and objective response rate (ORR), the second endpoints included diseases down staging, surgical outcomes, disease-free survival (DFS) and overall survival (OS). Results: A total of 58 patients were enrolled. Female accounted for 62.1% and most of them (77.6%) were never-smoker. Forty-five (77.6%) patients received the first generation of EGFR-TKI and 11 received the third. The median duration of EGFR-TKI before surgery was 3.6 months (0.7-19.5m). Nine (15.5%) patients achieved MPR and one patient (1.71%) achieved pathological complete response (pCR). The ORR was 60.3% (35/58) according to RECIST v1.1. Eighteen patients achieved TNM downstaging with T downstaging occurred in 44.8% of patients and N downstaging was about 32.8%. Majority of patients (96.6%) underwent thoracoscopic surgery and the rate of R0 resection was 82.8% (48/58). The DFS and OS of the whole cohort was 25.7months and not reached respectively. Patients with MPR had statistically improved outcomes than those without. What noticeable was that patients with tumor regression grade 3 (13/58) (residual viable tumor cells counts for 10% to 50%) also demonstrated a significant benefit from EGFR-TKI preoperative treatment than those with TRG4 or 5 (residual viable tumor cells&gt;50%) (p = 0.01). We define patients with TRG1 to TRG3 as deep pathological regression (DPR) and the rest as non-DPR, and the DPR cohort showed significantly prolonged DFS than those with non-DPR (median DFS, 60.9 vs 16.7 months; HR, 0.29 (95%CI: 0.11-0.74), p = 0.006), the data of OS was not mature. Subgroup analysis validated DPR was an independent predictive factor for DFS. Conclusions: EGFR-TKI as neoadjuvant therapy had good effect on tumor pathological regression and disease downstaging, DPR patients were more likely to achieve long-term disease-free survival. Patients with NDPR should be closely followed up and appropriate adjuvant therapy was necessary after surgery due to the high risk of reccurence.

Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: Results from a randomized, open-labeled, phase Ib study.

3505 Background: Immune checkpoint inhibitors have been used in neoadjuvant setting and showed promising clinical benefits in various tumors. Herein, we evaluate IBI310 plus sintilimab as neoadjuvant treatment in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) colorectal cancer (CRC) in a randomized, open-labeled, phase Ib study. Methods: Previously untreated pts with locally advanced (stage IIB-III), resectable, MSI-H/dMMR CRC were enrolled and randomized to receive 1 cycle of IBI310 1mg/kg plus 2 cycles of sintilimab 200 mg Q3W (arm A) or 2 cycles of sintilimab 200 mg Q3W (arm B) as neoadjuvant treatment. The stratification factors were risk evaluation at baseline (high risk: stage T4 or N2 vs low risk: stage T1-3 and N1) and age ( &lt; 55 years vs ≥55 years). Curative resection was scheduled on day 36 to 56 after first dose of neoadjuvant treatment. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included R0 resection rate and safety. Results: As of February 4, 2024, 101 pts were enrolled (males: 55.4%, median age: 56 years, ECOG PS 1: 54.5%, high risk: 76.2%) and randomized into arm A (n = 52) and arm B (n = 49). In arm A, 1 pt had early termination of treatment (withdrawal). In arm B, 4 pts had early termination of treatment (1 withdrawal, 1 died, 2 continued neoadjuvant sintilimab). Scheduled curative resection were performed in 51 (98.1%) pts in arm A and 45 (91.8%) pts in arm B. Postoperative evaluation revealed mismatch repair-proficient (pMMR) in 1 pt each in arm A and arm B. The pCR rates were 80.0% (40/50, 95%CI: 66.3-90.0) in arm A vs 47.7% (21/44, 95%CI: 32.5-63.3) in arm B (p = 0.0007). All pts received surgery had R0 resection. Median time between first dose of neoadjuvant treatment and surgery was 47 days (range: 35-82). Surgery delay occurred in 3 pts including 2 pts in arm A due to grade 2 hypothyroidism (2 days delay) and grade 1 hyperthyroidism (13 days delay), and 1 pt in arm B for other reason (26 days delay). Treatment-emergent adverse events (TEAEs) occurred in 46 pts (88.5%, grade≥3 in 13 pts) in arm A and 39 pts (79.6%, grade≥3 in 9 pts) in arm B. Immune-related adverse events (irAEs) occurred in 22 pts (42.3%) in arm A and 18 pts (36.7%) in arm B. Grade ≥3 irAEs occurred in 3 pts in arm A, including immune-mediated myocarditis, ileus and enteritis, and in 4 pts in arm B, including alanine aminotransferase increased, rash, hypothyroidism and myocarditis. Serious TRAEs occurred in 4 (7.7%) pts in arm A and 3 (6.1%) pts in arm B. TRAE leading to death occurred in 1 pt in arm B (myocarditis). Conclusions: Neoadjuvant IBI310 plus sintilimab significantly improved pCR rate than sintilimab alone in MSI-H/dMMR CRC. The safety profiles were comparable and manageable in both treatment arms. Clinical trial information: NCT05890742 .

SOGUG-NEOWIN: A phase 2, open-label, multi-centre, multi-national interventional trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) whose tumours express FGFR gene alterations.

TPS4623 Background: The standard treatment for nonmetastatic MIBC is neoadjuvant cisplatin-based therapy followed by radical cystectomy (RC). However, many patients are ineligible for cisplatin. Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for metastatic urothelial cancer (mUC), including for cisplatin-ineligible patients. Based on these results, ICIs are being explored as neoadjuvant treatment in resectable UC with preliminary data suggesting antitumour activity. ERDA is a Fibroblast Growth Factor Receptor (FGFR) inhibitor, which has shown efficacy in advanced UC with select FGFR2/3 mutations/fusions. ERDA plus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed FGFR-altered mUC in the phase 2 NORSE trial. We hypothesize that ERDA plus cetrelimab will improve the pathological complete response (pCR) rate in patients with FGFR+ MIBC who are candidates for RC and are ineligible for or refuse neoadjuvant cisplatin-based therapy. Methods: SOGUG-NEOWIN is a prospective, non-comparative, open label, multicentre, international trial to assess the efficacy of 9 or 12 weeks of neoadjuvant ERDA (cohort 1) or the combination of cetrelimab and ERDA (cohort 2) in patients with MIBC (cT2-Ta N0/1 M0) and FGFR alterations. Key eligibility criteria include ECOG PS 0-1; pure or predominant UC histology; decline or ineligible for cisplatin-based chemotherapy as defined by one of the following criteria: impaired renal function (GFR &lt; 60 mL/min), ≥ grade 2 hearing loss, or ≥ grade 2 peripheral neuropathy; patients are considered fit for cystectomy; no prior FGFR-targeted or anti-PD-(L)1 therapy; no prior systemic therapy, radiation or surgery (except TURBT or biopsies) for bladder cancer; prior BCG was allowed if completed ≥ 6 weeks before initiation of study treatment; no current retinopathy. A total of 45 patients will be allocated to each cohort by a centralized system. Co-primary endpoints are pCR rate and percentage of pathological downstaging response (&lt;ypT2). Secondary endpoints include event-free survival, overall survival, overall response rate, safety, tolerability, and delay to surgery. Biomarkers of response and resistance will be assessed using baseline archival tissues, blood and urine. Quality of life (QoL) will be assessed using FACT-Bl and EQ-5D-5L. Tumour response assessment via PET-MRI will be performed in a subset of patients. The trial is approved in 4 countries. The first patient was included on 31-Jan-2024. This trial would be the first to systematically address whether ERDA ± cetrelimab improves pCR in patients with FGFR-positive MIBC. (EudraCT 2022-002586-15). Clinical trial information: 2022-002586-15.

A phase II trial comparing dalpiciclib in combination with letrozole versus standard chemotherapy as neoadjuvant therapy in patients with high-risk HR- positive HER-2 negative breast cancer: DARLING-02.

TPS626 Background: Dalpiciclib is a CDK4/6 inhibitor that has shown promising efficacy and safety when in combination with endocrine in the treatment of advanced HR+ HER2- breast cancer. Building on preliminary findings from our previous study (Geng, 2023SABCS PO2-02-05), we aim to evaluate the efficacy and safety of dalpiciclib combined with letrozole versus standard chemotherapy as neoadjuvant treatment in patients with high-risk early breast cancer (EBC). Methods: This is a prospective, multicenter, randomized phase II non-inferiority trial. Main eligibility criteria include: female patients ≥18 years, ECOG performance status of 0-1, histologically confirmed invasive breast cancer, clinical stage T1c-T2, cN1–2 or T3-4, cN0-2, ER≥50%, HER2-negative, and Ki67 ≤ 20%. Participants are randomized 1:1 to receive either 24-week experimental intervention (oral dalpiciclib 150mg once daily for 3 weeks on, 1 week off and oral letrozole 2.5 mg/day) or 24-week standard intervention (intravenous epirubicin 100 mg/m² and intravenous cyclophosphamide 500 mg/m² on day 1 for three 3-week cycles, followed by intravenous docetaxel 100 mg/m2 on day 1 for three 3-week cycles). The primary endpoint is the objective response rate (ORR) assessed by RECIST v1.1. Secondary endpoints include patient-reported outcomes (EORTC QLQ-C30, EORTC QLQ-BR23), residual cancer burden 0–I rate, preoperative endocrine prognostic index score 0 rate, pathological complete response rate , 2-year invasive disease-free survival rate, and safety. Exploratory endpoints include biomarker analysis. The hypothesis is that the experimental group will not be inferior to control group. Assuming an ORR of 70% for both groups, a sample size of 65 patients per group is required to achieve 80% power to detect a non-inferiority margin of up to 20% at a two-sided significance level of 5%. A total of 130 patients are needed (65 per group). Considering a dropout rate of 10% per group, the total sample size is approximately 144 patients. The trial was registered at ClinicalTrials.gov (NCT06107673) and is actively recruiting. Clinical trial information: NCT06107673 .

Preliminary results from a multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).

e16595 Background: To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting. The preliminary results would be reported this time. Methods: This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). 51 patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive MIBC will be included. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Treatment efficacy will be performed by imaging and transurethral resection of tumors after the neoadjuvant treatment. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety. The secondary endpoints are disease control rate (DCR), overall survival (OS), local recurrence free survival (LRFS), distant metastasis free survival (DMFS) and quality of life. Results: Until now, 18 patients were included successfully, with 3 female patients and 15 male patients. And the median age was 64.47 years old. Of them, 7 patients were HER2(2+), and 11 patients were HER2(3+). The clinical stages were T2-4aN0-3M1a. Sixteen patients had the primary efficacy evaluation by now. After the neoadjuvant treatment, 7 patients were T0, 4 patients Tis, 2 patients partial response (PR), 2 patients stable disease (SD) and 1 patient suffered from progress of local disease. Hence the cCR rate was 68.75%, and the DCR was 90.91%. Fourteen patients chose radiotherapy as bladder-sparing therapy and no evidence of tumor in 6 patients who received treatment efficacy after radiotherapy. Two patients received radical cystectomy and pT3N0M0 was achieved for both. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 myositis, grade 1 elevated transaminase and grade 1 hyperthyroidism which led to treatment interruption of tislelizumab. And 10 patients experienced RC48-ADC related toxicities, including grade 1 elevated transaminase, grade 1 erythra and grade 1 paresthesia. No treatment related dose reduction happened. Conclusions: The novel neoadjuvant combination of RC48-ADC and tislelizumab showed promising down stage efficacy in patients with HER2 positive locally advanced MIBC and the toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiECRCT20210564.

Associations of ctDNA clearance and pathological response after neoadjuvant treatment in patients with locally advanced oral cancer.

6043 Background: Neoadjuvant treatment (NAT) has improved clinical outcomes in some patients with locally advanced oral squamous cell carcinoma (LAOSCC). Effective biomarkers assessing the treatment response is still lacking. Previous studies have posed the potential of circulating tumor DNA (ctDNA) in monitoring treatment response, but the underlying mechanisms behind non-shedding in tumors remain unclear. Methods: 29 LAOSCC patients received NAT followed by surgery were enrolled. Seven (24.1%), 9 (31%), and 13 (44.8%) patients received NAT of apatinib+camrelizumab, TPF chemoagents, and toripalimab+paclitaxel+cisplatin, respectively. Tumor tissues before NAT underwent whole exome sequencing and whole transcriptome resequencing. Blood samples at pre-NAT (T0), mid-NAT (T1), before surgery (T2) and after surgery (T3) were analyzed using a tumor-informed, personalized NGS assay. Multi-omics analysis, including ctDNA status, was performed with patients' clinical features and outcomes. Results: Among the 29 patients received NAT, the MPR rate was 55.2% (16/29), and the pCR rate was 27.6% (8/29). At baseline(T0), ctDNA was detectable in 25/29 (86.2%) patients, which decreased over time (T1: 77.8%; T2: 51.7%; T3: 6.9%). Persistent ctDNA at T2 indicates a higher rate of residual disease after NAT (100% non-pCR) compared to ctDNA-negative patients (42.8% non-pCR; p = 0.0047). All patients achieving pCR at T2 were ctDNA-negative (n=8, 100%) including 2 non-shedders. The PPV and NPV for predicting pCR by ctDNA clearance at T2 were 57.1% (8/14) and 100% (15/15), respectively. ARSF, CFAP47, or HAUS8 mutations at baseline were associated with significantly higher pCR rates (p&lt;0.05). Four non-shedders with undetectable ctDNA at T0 were significantly enriched in patients with negative lymph nodes, lower clinical T stage, and high CPS score. The non-shedders had significantly lower tumor mutational burden (TMB), higher stromal score and cancer-associated fibroblast (CAF) (p&lt;0.05). Spatial transcriptome analysis further supports that MHC-II pathway-related genes were significantly up-regulated in the non-shedders. The enhancing communication intensity between CAFs, endothelial cells and T cells might provide an anti-cancer immune microenvironment for non-shedders. Conclusions: Our results indicate that the clearance of ctDNA clearance at T2 was associated with an improved pCR rate. Furthermore, our findings shed light on the factors that prevent ctDNA release from oral squamous cell carcinoma.[Table: see text]

Prognostic significance of HER2 loss after HER2-targeted neoadjuvant treatment in patients with HER2-positive locally advanced breast cancer

Loss of human epidermal growth factor receptor 2 (HER2) expression can be seen in almost 25–30 % patients after HER2 receptor directed neoadjuvant treatment. These patients have unclear clinical outcomes in previous studies. We aimed to investigate the importance of HER2 loss, additionally with predictive factors for the loss of HER2. This was a retrospective and multicenter study that included 272 HER2-positive BC patients with no pathological complete response who received neoadjuvant chemotherapy plus HER2-targeted treatments. The factors that may affect the loss of HER2 detected by immunohistochemistry(IHC) and the association with survival were analyzed.The rate of HER2 loss after neoadjuvant treatments(NAT) was 27.9 % (n = 76). Disease recurrence was observed in 18(23.7 %) patients with HER2 loss, while it was detected in 62 (31.7 %) patients without HER2 loss(p = 0.23). Pre and post-NAT ER status, and post-NAT ki-67 status had a significant impact on disease-free survival(DFS) (p = 0.0012, p = 0.004, and p = 0.04, respectively).There were no significant association between DFS and loss of HER2 (p = 0.64) and dual anti-HER2 blockade (p = 0.21). Pre-NAT clinical stage (HR:1.65 p = 0.013), post-NAT LN status (HR:3.18, p = 0.02) and pre-NAT ER status (HR:0.24, p = 0.041) were significant independent prognostic factors for DFS while post-NAT residual disease in axillar tissue was an independent prognostic factor for OS (HR:1.54 p = 0.019). Moreover, age (<40 years vs ≥40 years) (p = 0.031) and tumor grade (p = 0.004) were predictive factors for HER2 loss. Our results showed that HER2 loss did not affect survivals. However, young age and being high grade tumor may predict HER2 loss.

Comparing niraparib versus platinum-taxane doublet chemotherapy as neoadjuvant treatment in patients with newly diagnosed homologous recombination–deficient stage III/IV ovarian cancer: study protocol for cohort C of the open-label, phase 2, randomized controlled multicenter OPAL trial

BackgroundMaintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib’s efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination–deficient tumors.MethodsOPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator’s discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator’s discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination–deficient. The primary endpoint is the pre–interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1.DiscussionOPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination–deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery.Trial registrationClinicalTrials.gov NCT03574779. Registered on February 28, 2022.

Neoadjuvant Immunotherapy Effectiveness in Patients With Microsatellite Instability-High (MSI-H) Gastric Cancer.

Purpose This research work evaluates monotherapy with checkpoint inhibitors (CPI). as a neoadjuvant treatment for patients with Microsatellite Instability-High (MSI-H) locally advanced gastric cancer. Methods Here we present the results of the retrospective study from Napalkov Cancer Center over 4.5 years on patients with MSI-H locally advanced gastric cancer. A total of 566 patients were analyzed, 18 of whom were included in the research, focusing on clinical response rate, surgical pathology, 'watch and wait' strategy, and safety outcomes on an exploratory basis. Patients were assigned to four to eight neoadjuvant cycles of CPI, followed by surgery. Results The objective response to neoadjuvant CPI in patients with MSI-H gastric cancer was 77.8%. Complete response was achieved in five (27.8%) and partial response in nine (50%) patients, accordingly. Surgery was performed on 14 patients. Complete margin-free (R0) resection rates were 100%. Downstaging was observed in 12 out of 14 patients. Histopathologic complete response rates (pathologic complete response or Tumor Regression Grade-major response (TRG1)) were achieved in eight (57.1%) patients. No disease progression was detected with a median follow-up of 33.7 months (4.4-55.7 months). Clinically significant adverse events were not observed. Conclusion CPI in a neoadjuvant setting for patients with MSI-H locally advanced gastric cancer is highly effective and safe.

A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study

BackgroundBiliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8).MethodsPURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study.Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate.Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis.DiscussionConsidering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery.Trial registrationPURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

Real-world experience with pertuzumab and trastuzumab combined with chemotherapy in neoadjuvant treatment for patients with early-stage HER2-positive breast cancer: the NEOPERSUR study

PurposeHER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC.MethodsA retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR).ResultsA total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3–7.7) and 7.3 (95% CI 7.1–7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3–4 anti-HER2 related toxicities were reported in six (1.9%) patients.ConclusionNeoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.

Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer.

The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC). The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety. A total of 74 631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments. Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.

Molecular and Clinicopathological Biomarkers in the Neoadjuvant Treatment of Patients with Advanced Resectable Melanoma.

Neoadjuvant systemic therapy is emerging as the best medical practice in patients with resectable stage III melanoma. As different regimens are expected to become available in this approach, the improved optimization of treatment strategies is required. Personalization of care in each individual patient-by precisely determining the disease-related risk and the most efficient therapeutic approach-is expected to minimize disease recurrence, but also the incidence of treatment-related adverse events and the extent of surgical intervention. This can be achieved through validation and clinical application of predictive and prognostic biomarkers. For immune checkpoint inhibitors, there are no validated predictive biomarkers until now. Promising predictive molecular biomarkers for neoadjuvant immunotherapy are tumor mutational burden and the interferon-gamma pathway expression signature. Pathological response to neoadjuvant treatment is a biomarker of a favorable prognosis and surrogate endpoint for recurrence-free survival in clinical trials. Despite the reliability of these biomarkers, risk stratification and response prediction in the neoadjuvant setting are still unsatisfactory and represent a critical knowledge gap, limiting the development of optimized personalized strategies in everyday practice.

Efficacy and safety of disitamab vedotin combined with toripalimab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer.

631 Background: For HER2 positive muscle-invasive bladder cancer (MIBC), the efficacy of cisplatin-based NAC is unsatisfied, and adverse reactions are inevitable or even intolerable. Disitamab vedotin is an antibody-drug conjugate composed of an anti-HER2 antibody disitamab and MMAE payload. Multiple clinical studies have confirmed that promising activity in HER2-positive locally advanced or mUC patients。This study aims to evaluate the safety and efficacy of disitamab vedotin, and toripalimab as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced MIBC. Methods: In this Study, Platinum intolerance and pathological andimaging diagnosed cT2-4bN0M0 MIBC patients with HER2 positive (HER2 IHC2+ or HER2 IHC3+) received 3 cycles toripalimab (200mg, iv, D1, Q2W) combined with disitamab vedotin (2mg/kg, iv, D1, Q2W). The primary endpoint was pCR, and the secondary endpoints included PFS, OS, and safety. Results: From July 2023 to Sep 2023, 12 patients were enrolled. The median age was 68 (55-82) years . By the data cut off in August 2023, the primary end point pCR was 80% (8/10). Median follow-up time was 4.2 (2.2-8.45) month. The median overall survival (OS) was not reached，ORR was100%. In terms of safety, the treatment-related adverse events (TRAEs) of any grade occurred in ten patients (83.3%), and the most common TRAEs were nausea (58.3%), followed by alopecia (33.3%), diarrhea (16.7%) and Cardiac tachycardia (8.3%). most of which are grade 1-2. Grade 3 TRAE is Cardiac tachycardia and occurred in one patient. No grade 4 and 5 TRAEs were observed. Conclusions: From July 2023 to Sep 2023, 12 patients were enrolled. The median age was 68 (55-82) years . By the data cut off in August 2023, the primary end point pCR was 80% (8/10). Median follow-up time was 4.2 (2.2-8.45) month. The median overall survival (OS) was not reached, ORR was100%. In terms of safety, the treatment-related adverse events (TRAEs) of any grade occurred in ten patients (83.3%), and the most common TRAEs were nausea (58.3%), followed by alopecia (33.3%), diarrhea (16.7%) and Cardiac tachycardia (8.3%). most of which are grade 1-2. Grade 3 TRAE is cardiac tachycardia and occurred in one patient. No grade 4 and 5 TRAEs were observed.

Quantitative analysis of contrast-enhanced ultrasound in neoadjuvant treatment of locally advanced rectal cancer: a retrospective study.

To explore the clinical value of contrast-enhanced ultrasound (CEUS) quantitative analysis in the evaluation and prognosis of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Eighty-three consecutive patients undergoing neoadjuvant chemoradiotherapy and total mesorectal excision for LARC were retrospectively included. According to pathological results, patients were categorized into complete or incomplete response groups. Differences in ultrasonic parameters, pathological results, and clinical data between groups were evaluated. The cutoff point for a complete response as determined by quantitative analysis of CEUS was assessed using a receiver operating characteristic curve; additionally, overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 83 patients, 12 (14.5%) achieved a complete response and 71 (85.5%) did not. There were significant between-group differences in carcinoembryonic antigen (CEA) levels, differentiation degree, proportion of tumor occupying the lumen, anterior-posterior and superior-inferior diameters of the lesion, and intensity of enhancement (P<0.05). CEUS quantitative analysis showed significant between-group differences in peak intensity (PI) and area under the curve (AUC) values (P<0.05). The OS and PFS of patients with high PI, high AUC value, and poorly differentiated cancer were significantly worse than those with low PI, low AUC values, and moderately to highly differentiated cancer (P<0.05). High CEA levels (hazard ratio: 1.02, 95% confidence interval: 1.01-1.04; P=0.002) and low differentiation (2.72, 1.12-6.62; P=0.028) were independent risk factors for PFS and OS. CEUS can predict the response to neoadjuvant treatment in patients with LARC. CEUS quantitative analysis is helpful for clinical prognosis.