Cancer treatment and research communications最新文献

Background

In untreated ALK-positive non-small cell lung cancer no randomized controlled trials (RCTs) are available directly comparing next-generation ALK-inhibitors. We conducted a sensitivity analysis using the likelihood of being helped or harmed (LHH).

Methods

Phase III trials comparing ALK-inhibitors to crizotinib were included. Efficacy outcomes were progression-free survival (PFS), objective response rate (ORR), PFS in patients with brain metastases and intracranial ORR. Safety outcomes were grade 3–4 adverse events (AEs), dose reductions and discontinuations.

Results

Six RCTs (1524 patients) were included. Lorlatinib and brigatinib had the lowest NNT for intracranial outcomes. Alectinib demonstrated favourable LHHs for grade 3–4 AEs, dose reductions and discontinuations. Brigatinib LHHs were low for common AEs, mainly laboratory anomalies and hypertension. Ensartinib showed mainly skin toxicity. Lorlatinib LHHs were low for specific grade 3–4 AEs, mainly metabolic alterations.

Conclusions

The four ALK-inhibitors exhibited favourable risk-benefit ratios. Lorlatinib showed the lowest NNT for systemic efficacy and, alongside with Brigatinib, lower NNTs for intracranial efficacy. Alectinib exhibited higher LHHs for AEs.

Registration

PROSPERO registration number: CRD42023389101.

Objectives

The incidence of cervical cancer increases every year during pregnancy. Cervical cytology in pregnant women has a unique morphology and liquid-based cytology methods are prone to cause false positives. The aim of this study was to investigate the serum cytokeratin 19 fragment antigen 21–1 (CYFRA21–1) and squamous cell carcinoma associated antigen (SCC-Ag) concentrations in healthy pregnant women during pregnancy and to assess their diagnostic value for cervical cancer in pregnancy.

Methods

In this prospective study, 165 healthy non-pregnant women, 441 healthy pregnant women and 22 patients with cervical cancer in pregnancy were recruited. The healthy pregnant women group included 143 women in the first trimester (T1), 147 in the second (T2) and 151 in the third (T3).

Results

Both SCC-Ag and CYFRA21–1 levels were significantly different in the healthy pregnant women group compared to the control group. The CYFRA21–1 and SCC-Ag were higher in the T1 and T3 than in the control groups. However, there was no statistically significant difference in serum CYFRA21–1 and SCC-Ag levels in the T2 group compared to the control group. The AUCs of CYFRA21–1, SCC-Ag and CYFRA21–1 combined with SCC-Ag were 0.674, 0.792, and 0.805, respectively. The cut-off values of CYFRA21–1 and SCC-Ag were 6.64 ng/mL and 1.75 ng/mL, respectively.

Conclusions

Serum CYFRA21–1 and SCC-Ag levels were higher in pregnant women during early and late pregnancy compared to non-pregnant individuals, while they were not statistically different from non-pregnant women during mid-trimester. CYFRA21–1 and SCC-Ag have diagnostic value for cervical cancer in pregnancy.

Introduction

We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors.

Materials and methods

This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle.

Results

Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease.

Conclusions

Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown.

Trial registration

ClinicalTrials.gov, NCT04462952

Purpose

This study aims to evaluate the association between surgical margin status and local recurrence of DCIS.

Methods

A retrospective analysis of a prospectively maintained 20-year DCIS database was performed. >=2 mm margin was defined as clear margin. Local relapse rate between the patients with clear versus close margins were analyzed with Kaplan-Meier analyses.

Results

654 patients were analyzed. Median age was 46.5 (Range 18 – 80). 205 (31.3%) were high grade, 194 (29.7%) were intermediate grade, 143 (21.9%) were low grade. 112 (18.3%) were unknown. 202 (30.9%) were estrogen receptor positive, 49 (7.4%) were negative, 403 (61.6%) patients were unknown.

403 (61.6%) patients received mastectomy while 251 (38.4%) patients received BCS and radiotherapy. 549 (83.9%) patients had clear surgical margin, 50 (7.7%) patients had involved (positive) resection margin, 55 (8.4%) had close margin (<2 mm margin). All patients with involved margin received re-excision of margin, while 21 patients (out of 55 who had close resection margins) received re-excision of margin. Negative surgical margins were achieved after the re-excision. 34 patients with close resection margin decided not to receive re-excision but to undergo adjuvant radiotherapy.

After median follow-up of 128 months, the 10-year ipsilateral breast tumor relapse (IBTR) was 4.5% (N = 28), Of which 27 (96.4%) patients had clear margin after the initial surgical treatment of DCIS. 1 (3.6%) patient had close surgical margin. Difference in IBTR between the two groups was not statistically significant (p = 0.692).

Conclusion

Close surgical margin for DCIS is not associated with increased risk of IBTR.

The management of periocular basal cell carcinoma (BCC) is challenging due to its proximity to the eyeball. Vismodegib, a Hedgehog pathway inhibitor, has emerged as a therapeutic option for locally advanced and metastatic BCC. To critically appraise the relevant evidence, we conducted a systematic review of observational and experimental studies assessing the efficacy and safety of vismodegib for periocular BCC. Thirty-seven trials, including 435 patients, were eligible. No randomized trials were retrieved. Complete and overall clinical response rates were 20–88 % and 68–100 %, respectively. Disease progression was observed at a maximum rate of 14 %. Recurrence rates varied between 0 % and 31 %. The most common side effects were muscle cramps, dysgeusia, weight loss and alopecia. Treatment with vismodegib improved health-related quality of life. In conclusion, vismodegib represents an important novel treatment for advanced periocular BCC, with good response rates and acceptable tolerability profile. Nevertheless, its full potential needs clarification through randomized controlled trials.

Background

NY-ESO-1 and XAGE1 cancer/testis antigens elicit humoral and cellular immune responses in NSCLC patients. We aimed to predict clinical benefit with ICI monotherapy, using an automated immunoassay of NY-ESO-1/XAGE1 antibodies (Abs).

Methods

This study enrolled 99 NSCLC patients who received nivolumab after chemotherapy, including 21 patients harboring EGFR, ALK, or KRAS alterations. The cutoff value (10 units/mL) of NY-ESO-1 and XAGE1 Ab was determined based on Ab levels in non-malignant controls, and NY-ESO-1/XAGE1 Abs in NSCLC were measured before nivolumab. Differences in PFS and OS between the Ab-positive and Ab-negative groups were retrospectively analyzed using Cox regression analysis after applying inverse probability of treatment weighting (IPTW).

Results

NY-ESO-1/XAGE1 Abs were positive in 28 NSCLC, who responded more highly to nivolumab than the Ab-negatives (response rate 50.0% vs. 15.5 %, p < 0.0007). The IPTW-adjusted positives and negatives for NY-ESO-1/XAGE1 Abs were 24.5 and 70.2, respectively. The Ab-positives showed longer IPTW-adjusted PFS (HR = 0.59, 95 % CI: 0.39–0.90, p = 0.014) and IPTW-adjusted OS (HR = 0.51, 95 % CI: 0.32–0.81, p = 0.004) than the Ab-negatives. Among NSCLC harboring driver genes, the Ab-positives (n = 10) showed longer PFS (HR = 0.34, 95 % CI: 0.13–0.89, p = 0.029) and OS (HR = 0.27, 95 % CI: 0.098–0.75, p = 0.012) than the Ab-negatives (n = 11).

Conclusion

Our immunoassay of NY-ESO-1/XAGE1 Abs is probably useful for predicting the clinical benefit with nivolumab in NSCLC, including those harboring driver genes. These results suggest that our immunoassay may be useful in ICI monotherapy for NSCLC.

Cervical cancer (CC) remains one of the most common and deadly malignancies among women worldwide, with exceptionally high morbidity and mortality rates. The aberrant activation of the hedgehog pathway is intimately associated with tumor development and progression. Nevertheless, the potential therapeutic targets within the hedgehog pathway in CC have yet to be clearly identified. In this study, we conducted an in-depth investigation of hedgehog pathway-related genes in CC, integrating single-cell sequencing data and spatial transcriptomics. Utilizing a comprehensive scoring algorithm, we identified that myofibroblasts within CC tissue exhibit a highly enriched hedgehog pathway. Our analysis of the myofibroblast development process revealed that MYH9 plays a crucial role. Further exploration using spatial transcriptome data allowed us to delve into the role of MYH9 in myofibroblasts. We discovered that MYH9-negative and MYH9-positive myofibroblasts display distinct profiles. Validation using extensive transcriptome data demonstrated that a high infiltration of MYH9-positive myofibroblasts is a risk factor for CC patients, significantly impacting prognosis and immunotherapeutic efficacy. Our study provides unique insights into the relationship between CC and the hedgehog pathway, offering new directions for cancer treatment strategies.

Objective

Patients with persistent, recurrent, or metastatic cervical cancer have poor prognosis. While recent advances have expanded treatment options, real-world data on treatment patterns and outcomes in this population are lacking.

Methods

This retrospective study identified adult females with persistent, recurrent, or metastatic cervical cancer from the ConcertAI Oncology Dataset who received systemic therapy on or after August 15, 2014. Patients were followed from persistent, recurrent, or metastatic diagnosis through third-line (3 L) therapy, death, end of record, or study end (June 2021). Data collection included patient characteristics, treatment patterns, and clinical outcomes. Kaplan-Meier methods were used for the three most common first-line (1 L) regimens to analyze real-world time on treatment (rwToT), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS). Analyses were stratified by bevacizumab receipt by treatment line.

Results

307 patients were included (mean [standard deviation] age 51.5 [13.2] years, 70.7% White). 91.2% of patients had metastatic disease, 8.5% had persistent disease, and <1% had recurrent disease. The most common 1 L regimen was carboplatin+paclitaxel+bevacizumab (40.7%) with median (95% confidence interval [CI]) rwToT of 3.5 (2.9–4.4) months. 57.0% of patients proceeded to second line (2 L), and 25.7% went to 3 L. Median (95% CI) rwPFS was 7.2 (6.4–8.1) months, and median (95% CI) rwOS was 16.5 (14.2–19.9) months, from initiation of 1 L.

Conclusions

1 L regimens received in patients with persistent, recurrent, or metastatic cervical cancer generally followed clinical guidelines, and the rwOS agrees with clinical trials. This study highlights the burden of disease and unmet need for specific treatments in these patients.

Background

Elevated platelet lymphocyte ratio (PLR) and low body mass index (BMI) are associated with inferior survival in non-small cell lung cancer (NSCLC) patients receiving immunotherapy (IO). We evaluated real-world prognostic utility of PLR, BMI, and albumin level in stage IV NSCLC patients receiving first line (1L) IO.

Methods

We identified 75 stage IV patients who received 1L IO therapy at USC Norris Comprehensive Cancer Center and Los Angeles General Medical Center from 2015 to 2022. The primary outcome was overall survival (OS) from time of IO with attention to pre-treatment BMI < 22, albumin < 3.5 g/dL, and PLR > 180.

Results

Median age was 66.5 years with 49 (65.3%) males. 25 (33.3%) had BMI < 22. 45/75 (60%) had PLR > 180. Patients with BMI < 22 had inferior OS (13.1 months (m) vs. 37.4 m in BMI > 28, p-value = 0.042) along with patients with albumin<3.5 g/dL (OS: 2.8 m vs. 14.6 m, p-value = 0.0027), and patients with PLR>180 (OS: 8.7 m vs. 23.0 m, p = 0.028). Composite BMI < 22, PLR > 180 had the worst OS, p-value = 0.0331. Multivariate analysis controlling for age, smoking, gender, PD-L1 tumor proportion score (TPS), and histology (adenocarcinoma, squamous, adenosquamous, and large cell) showed that BMI (HR: 0.8726, 95% CI: 0.7892–0.954) and PLR > 180 (HR: 2.48, 95% CI: 1.076–6.055) were significant in OS mortality risk.

Conclusion

Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients receiving IO therapy of their prognosis and supportive care.

MicroAbstract

We evaluated real-world prognostic utility of platelet lymphocyte ratio (PLR), body mass index (BMI), and albumin level in 75 Stage IV NSCLC patients receiving first line IO. Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients of their prognosis and to emphasize supportive care needs.