Low-grade Cancer Research Articles

Abstract A091: The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors

Abstract KRAS mutations (mt) occur in up to 98% of pancreatic ductal adenocarcinoma (PDAC) and represent a key initiating event in PDAC carcinogenesis. Therapeutic efforts targeting the RAS/RAF/MEK/ERK (MAPK) pathway with MEK-only inhibitors have been unsuccessful in substantially modifying PDAC prognosis. Thus, novel strategies are needed to overcome putative mechanisms of resistance to MEK inhibition such as focal adhesion kinase (FAK) pathway activation. Another hallmark of PDAC is its high stromal density, which is thought to limit the penetration of cytotoxic drugs and T cells into the tumor and has been shown to be correlated with FAK hyperactivation, altogether supporting co-targeting the MAPK and FAK pathways to achieve deep and durable responses for patients with PDAC. Avutometinib is a RAF/MEK clamp that potently inhibits MEK kinase activity and induces dominant negative RAF-MEK complexes preventing phosphorylation of MEK by ARAF, BRAF and CRAF. This unique mechanism allows avutometinib to block MEK signaling without the compensatory re-activation of MEK that appears to limit the efficacy of MEK-only inhibitors. Preclinically, avutometinib has shown strong anti-proliferative potency across tumor cell lines carrying KRAS mt including PDAC cell lines. Clinically, avutometinib in combination with the FAK inhibitor (FAKi) defactinib received breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer. Here, we tested the combination of avutometinib and FAK inhibition with standard of care chemotherapy in PDAC mouse models. In a KRAS/p53 pancreatic cancer mouse model, we found that whereas the combination of avutometinib + FAKi induced tumor inhibition and increased survival, addition of chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) to avutometinib/FAKi induced tumor regression. These results support the ongoing clinical study of avutometinib and defactinib in combination with standard of care chemotherapy (gemcitabine/nab-paclitaxel) for patients with front-line metastatic PDAC (NCT05669482). Other combinations being explored preclinically include avutometinib with G12D inhibition (G12Di) in KRAS G12D PDAC, which accounts for 28% of patients with PDAC. In 3D culture, avutometinib was synergistic with the G12Di MRTX1133 in reducing viability of a panel of KRAS G12D PDAC cell lines. In mouse models, avutometinib enhanced anti-tumor efficacy of MRTX1133 in a KRAS G12D pancreatic cancer patient-derived xenograft model. Furthermore, in KRAS mt PDAC cell lines, avutometinib was synergistic with the autophagy inhibitors chloroquine or apilimod. Indeed, dual treatment with avutometinib + MRTX1333 synergistically decreased proliferation and increased autophagic flux in KRAS G12D PDAC cell lines, supporting testing the triple combination of avutometinib + G12Di + autophagy inhibitor in patients with KRAS G12D pancreatic cancers. In conclusion, we show that avutometinib is a unique RAF/MEK clamp with the potential to become the backbone of therapy for pancreatic cancers. Citation Format: Silvia Coma, Xiuting Liu, Noah L. Pieper, Wen-Hsuan Chang, Kirsten L. Bryant, Channing J. Der, David G. DeNardo, Jonathan A. Pachter. The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A091.

The Value of Negative Urinary Dipstick Tests for Haematuria in Patients Undergoing Surveillance for Low-grade Ta Urothelial Cancer: A Two-stage Prospective Clinical Study in 524 Patients

Background and objectiveThe risk of first recurrence beyond 5 yr for patients with low-grade (LG) Ta non–muscle-invasive bladder cancer (NMIBC) is low enough to consider discontinuing cystoscopic surveillance at that point. However, a positive urinary dipstick test for haematuria (UDH) during and beyond the period of cystoscopic surveillance can disrupt plans to cease surveillance because the association between UDH positivity and recurrence in LG Ta NMIBC is unknown. In a two-stage study, we evaluated this association and explored the role of UDH negativity in predicting the absence of recurrence. MethodsBecause of previously demonstrated changes in recurrence patterns over time, two prospective cohorts were assessed: an “exploratory” cohort (January 2007–March 2008) and a “validation” cohort (November 2017–August 2018). UDH was performed before flexible cystoscopy. Patient, operative, and surveillance data have been recorded prospectively using standard pro forma sheets since 1978 in our institution. Only patients with primary LG Ta pTa NMIBC were included for analysis. Key findings and limitationsWe assessed 231 patients in the exploratory group and 293 in the validation group. The proportion of smokers (67% vs 70%; p = 0.5) and mean follow-up (72.2 vs 79.9 mo; p = 0.2) were similar between the groups. The recurrence rate was higher in the exploratory group (19% vs 11%; p = 0.009), as was the UDH positivity rate (37% vs 11%; p < 0.001). The specificity and negative predictive value were 64% and 83% in the exploratory group, and 90% and 90%, respectively, in the validation group. These values increased further for the subgroup with solitary primary tumours the subgroup without recurrence for 3 yr. Conclusions and clinical implicationsUDH negativity has a high probability of being associated with the absence of recurrence in small LG Ta NMIBC and could be an inexpensive adjunct during surveillance. Ongoing validation, which started in 2019, is being performed in a now-nationalised Scottish protocol in which UDH replaces cystoscopy in years 2 and 4 for patients in the low-risk group. Patient summaryWe investigated the accuracy of a dipstick test for blood in the urine for patients undergoing surveillance for low-grade noninvasive bladder cancer. We found that a negative dipstick test result was highly associated with the absence of tumour recurrence, particularly for patients with the lowest risk. These findings have been introduced into a national protocol designed to reduce the frequency of telescopic inspection of the bladder during surveillance to reduce the burden for patients.

DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC. Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2’-7’-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB

Endometrioid carcinomas with sex cord-like formations and hyalinization: spontaneous pregnancy after conservative treatment

Endometrioid carcinoma with sex cord-like formations and hyalinization of the uterine corpus, or corded and hyalinized endometrioid adenocarcinoma (CHEC), is a rare morphological variant of endometrioid carcinoma, for which there is limited literature and few cases reports. Most researchers tend to consider CHEC as a low-grade cancer with a favorable prognosis. Full-staging surgery is the primary choice for this disease, and no case of CHEC has been previously reported to be treated conservatively. Here, we present the following case to explore the possibility of fertility-preserving treatment for young women with CHEC. A 23-year-old nulliparous patient diagnosed with presumed stage IA CHEC received fertility-sparing treatment at the Obstetrics and Gynecology Hospital of Fudan University and got a complete response (CR) after 10 months of conservative treatment. The patient subsequently became pregnant spontaneously, successfully conceived, and gave birth to a healthy male neonate without any sign of recurrence during 37 months follow-up after CR. The patient’s postpartum follow-up is continuing. Presently, CHEC is not included in the fertility-sparing field of any available guidelines. This case indicates that fertility-sparing treatment may be an option for highly selected patients with CHEC. Continuous follow-up remains mandatory to observe long-term outcomes.

Targeting BRAF pathway in low-grade serous ovarian cancer.

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS/BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma.

Low-Grade Serous Ovarian Cancer: Expert Consensus Report on the State of the Science

(Abstracted from Int J Gynecol Cancer 2023;0:1–14) Low-grade serous carcinoma represents less than 10% of epithelial ovarian cancers, is often diagnosed in younger women, and is associated with prolonged survival relative to high-grade serous carcinoma. In 2019, a panel of experts gathered to address the unique needs of low-grade serous carcinoma management and published a consensus paper.

Body Mass Index and Risk of Female Reproductive System Tumors Subtypes: A Meta-Analysis Using Mendelian Randomization.

Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577-1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216-1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.

1H magnetic resonance spectroscopy in the differentiation between low- and high-grade cervical carcinoma: is it efficient?

To evaluate the extent to which magnetic resonance spectroscopy (MRS) lipid metabolites are accurate in predicting high-grade cervical cancer. This prospective single-centre pilot study included 20 cases with pathologically proven cervical cancer. They underwent pelvic magnetic resonance imaging (MRI) with MRS. Two radiologists, blinded to the histopathological results, with 10 years of experience in gynaecological imaging, independently analysed the MRI images and MRS curves, and a third one resolved any disagreement. Using the histopathological results as a standard test, the receiver operating characteristics (ROC) curve was utilised to calculate the optimal lipid peak (1.3 ppm) cutoff for predicting high-grade cervical cancer. The difference in MRS metabolites between low- and high-grade cervical cancer groups was estimated using the Mann-Whitney test. The study included 11 high-grade and nine low-grade cervical cancer cases based on the histopathological evaluation. A lipid (1.3 ppm) peak of 29.9 was the optimal cutoff for predicting high-grade cervical cancer with 100% sensitivity, 77.8%, specificity, and 90% accuracy. Moreover, there was a significant difference between low- and high-grade cervical cancer cases concerning lipid peak at 0.9 ppm, lipid peak at 1.3 ppm, and the peak of choline with (p-value 0.025, 0.001, and 0.023), respectively. MRS might be considered a useful imaging technique for assessing the grade of cervical cancer and improving the planning of treatment. It shows a good diagnostic accuracy. Therefore, it can be adopted in clinical practice for better patient outcome.

The causal association between artificial sweeteners and the risk of cancer: a Mendelian randomization study.

Artificial sweeteners (ASs) have been widely added to food and beverages because of their properties of low calories and sweet taste. However, whether the consumption of ASs is causally associated with cancer risk is not clear. Here, we utilized the two-sample Mendelian randomization (MR) method to study the potential causal association. Genetic variants like single-nucleotide polymorphisms (SNPs) associated with exposure (AS consumption) were extracted from a genome-wide association study (GWAS) database including 64 949 Europeans and the influence of confounding was removed. The outcome was from 98 GWAS data and included several types of cancers like lung cancer, colorectal cancer, stomach cancer, breast cancer, and so on. The exposure-outcome SNPs were harmonized and then MR analysis was performed. The inverse-variance weighted (IVW) with random effects was used as the main analytical method accompanied by four complementary methods: MR Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses consisted of heterogeneity, pleiotropy, and leave-one-out analysis. Our results demonstrated that ASs added to coffee had a positive association with high-grade and low-grade serous ovarian cancer; ASs added to tea had a positive association with oral cavity and pharyngeal cancers, but a negative association with malignant neoplasm of the bronchus and lungs. No other cancers had a genetic causal association with AS consumption. Our MR study revealed that AS consumption had no genetic causal association with major cancers. Larger MR studies or RCTs are needed to investigate small effects and support this conclusion.

Low-grade versus high-grade serous ovarian cancer: comparison of surgical outcomes after secondary cytoreductive surgery.

Retrospective series have shown secondary cytoreductive surgery improves oncological outcomes in recurrent low-grade serous ovarian cancer. We aim to compare surgical procedures and complications between patients with low-grade and high-grade recurrent serous ovarian cancer. This retrospective single-institution study includes patients with recurrent low-grade and high-grade serous ovarian cancer undergoing surgery between January 2012 to December 2021. Patients were propensity matched 1:3 for residual tumor at first surgery, presence of ascites and performance status. Complexity of surgery and postoperative complications were analyzed. A total of 116 patients undergoing secondary cytoreductive surgery were included with 29 patients (25%) having low-grade ovarian cancer. The median age of the patients was 54 years (range: 19-85) and 57 years (range: 29-78) in low-grade and high-grade ovarian cancer, respectively (p=0.13). Stages III/IV at diagnosis were more frequent in patients with high-grade ovarian cancers (p<0.001). Peritoneal involvement was higher in low-grade compared with high-grade ovarian cancer as shown by the higher rate of diaphragmatic (41.4% vs 21.8%, p=0.05), abdominal wall (41.4% vs 18.4%, p=0.02) and pelvic (51.7% vs 21.8%, p=0.01) peritonectomy. Multiple bowel resections were higher in low-grade ovarian cancer (24.1% vs 8.0%, p=0.04), while high-grade ovarian cancer had a higher rate of nodal recurrences (73.2%% vs 37.9%, p=0.03). Overall, surgical complexity was higher in low-grade ovarian cancer (58.6% vs 36.8%; p=0.05), with higher median estimated blood loss (400 vs 200 mL; p=0.01) compared with high-grade. Complete cytoreduction was achieved in 26 patients (89.7%) with low-grade and 84 (96.6%) with high-grade (p=0.16) ovarian cancer, with no significant differences in postoperative complications. Secondary cytoreductive surgery in low-grade serous ovarian cancer patients was associated with higher complexity, multiple bowel resections, and higher median estimated blood loss than in high-grade serous ovarian cancer. The comparable rate of postoperative complications suggests that secondary cytoreductive surgery in this group of patients is feasible in expert centers.

Endoscopic excision versus radical nephroureterectomy for non-muscle invasive upper tract urothelial carcinoma: A population-based large cohort study

BackgroundAs an important kidney-sparing treatment for upper urothelial carcinoma (UTUC), whether endoscopic excision can be performed without sacrificing oncologic outcomes remains indefinite. This study aimed to investigate the prevalence and efficacy of endoscopic excision, in patients with non-muscle invasive UTUC (NMIUTUC) and compare them to those of radical nephroureterectomy (RNU). MethodsUsing the Surveillance, Epidemiology, and End Results database, we reviewed 4347 cases with NMIUTUC (cTis/Ta/T1-N0-M0,≤ 5.0 cm) between 2004 and 2020. Surgical treatment modalities included endoscopic excision and RNU. Propensity score matching analysis was used to minimize the selection bias between endoscopic excision and RNU, selecting 1:1 matched patients in the two group. ResultsA total of 794 patients with NMIUTUC were included after matching (397:397). Patients who underwent endoscopic excision had worse survival outcomes compared with those of patients who underwent RNU (5-year OS: 65.3 % vs. 80.3 %, p < 0.0001; 5-year DSS: 83.2 % vs. 94.0 %, p = 0.00021). After stratification by anatomical sites, the effect of endoscopic excision for NMI renal pelvis cancer was worse than RNU (5-year OS, 62.9 % vs. 82.8 %; 5-year DSS, 78.8 % vs. 91.6 %), while in NMI ureteral cancer, there is no statistically significant difference in OS and DSS between endoscopic excision and RNU. Further stratification according to tumor grade revealed equivalent tumor control effects of endoscopic excision and RNU in low-grade NMI ureteral cancer (5-year OS: 67.7 % vs. 72.5 %, p = 0.23; 5-year DSS: 87.2 % vs. 93.1 %, p = 0.17); while for renal pelvis tumor and high-grade ureteral tumor, endoscopic excision was related with significantly inferior prognosis. ConclusionsOnly for low-grade NMI ureteral cancer, endoscopic excision and RNU are oncologically equivalent, indicating that endoscopic excision might be an effective option for low-grade NMI ureteral cancer. This result needs to be further verified in randomized controlled trials.

Preoperative Grading of Rectal Cancer with Multiple DWI Models, DWI-Derived Biological Markers, and Machine Learning Classifiers.

Background: this study aimed to utilize various diffusion-weighted imaging (DWI) techniques, including mono-exponential DWI, intravoxel incoherent motion (IVIM), and diffusion kurtosis imaging (DKI), for the preoperative grading of rectal cancer. Methods: 85 patients with rectal cancer were enrolled in this study. Mann-Whitney U tests or independent Student's t-tests were conducted to identify DWI-derived parameters that exhibited significant differences. Spearman or Pearson correlation tests were performed to assess the relationships among different DWI-derived biological markers. Subsequently, four machine learning classifier-based models were trained using various DWI-derived parameters as input features. Finally, diagnostic performance was evaluated using ROC analysis with 5-fold cross-validation. Results: With the exception of the pseudo-diffusion coefficient (Dp), IVIM-derived and DKI-derived parameters all demonstrated significant differences between low-grade and high-grade rectal cancer. The logistic regression-based machine learning classifier yielded the most favorable diagnostic efficacy (AUC: 0.902, 95% Confidence Interval: 0.754-1.000; Specificity: 0.856; Sensitivity: 0.925; Youden Index: 0.781). Conclusions: utilizing multiple DWI-derived biological markers in conjunction with a strategy employing multiple machine learning classifiers proves valuable for the noninvasive grading of rectal cancer.

Aberrant nuclear β-catenin distribution does not prognosticate recurrences of endometrioid endometrial cancers – A retrospective single-institutional study

ObjectiveAberrant β-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer. MethodsThis retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed. Results297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant β-catenin distribution was found in 135 patients (45.5%) and wild type membranous β-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant β-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between β-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected. ConclusionsAberrant β-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.

Outcomes of Biopsy Grade Group 1 Prostate Cancer Diagnosis in the Danish Population

BackgroundDebate regarding a nomenclature change for grade group 1 (GG 1) prostate cancer to noncancer has been revived, as this could be a powerful tool in reducing the overtreatment of indolent disease. ObjectiveTo describe outcomes for all men diagnosed with GG 1 prostate cancer in the Danish population, with a focus on men followed conservatively. Design, setting, and participantsThis was a population-based observational study using data from the Danish Prostate Registry. Outcome measurements and statistical analysisWe measured the cumulative incidence of curative treatment, endocrine treatment, and cause-specific mortality. Results and limitationsThe cumulative incidence of endocrine therapy at 10 yr was 5.3% (95% confidence interval [CI] 4.3–6.3%) for men with initial active surveillance and 21% (95% CI 19–23%) for men with initial watchful waiting for localized GG 1. In the GG1 cohort, the prostate cancer–specific mortality rate at 15 yr was 14% (95 CI% 11–16%) for men on watchful waiting, 10% (95 CI% 6.7–14%) for men with prostate-specific antigen <10 ng/ml on watchful waiting, and 16% (95 CI% 13–19%) for men who did not receive curative-intent treatment or histological assessment. The study is limited by the historic nature of the observations over a period during which diagnostic procedures and treatments have evolved. ConclusionsGG 1 cancer can lead to disease-specific mortality in men with localized prostate cancer, and changing the nomenclature for all men may lead to undertreatment. Patient summaryKey opinion leaders have suggested that prostate cancers of Gleason grade group 1 (GG 1) should be renamed as noncancer to reduce overtreatment. The argument is that low-grade cancer does not metastasize. However, our nationwide population-based study showed that death from prostate cancer can occur in some men diagnosed with GG 1 disease. These men should be considered in discussions on changing the name for GG 1 prostate cancer.

Cancer Detection Rate and Abnormal Interpretation Rate of Prostate MRI in Patients With Low-Grade Cancer

PurposeThe aim of this study was to evaluate the utility of cancer detection rate (CDR) and abnormal interpretation rate (AIR) in prostate MRI for patients with low-grade prostate cancer (PCa). MethodsThis three-center retrospective study included patients who underwent prostate MRI from 2017 to 2021 with known low-grade PCa (Gleason score 6) without prior treatment. Patient-level highest Prostate Imaging Reporting & Data System (PI-RADS®) score and pathologic diagnosis within 1 year after MRI were used to evaluate the diagnostic performance of prostate MRI in detecting clinically significant PCa (csPCa; Gleason score ≥ 7). The metrics AIR, CDR, and CDR adjusted for pathologic confirmation rate were calculated. Radiologist-level AIR-CDR plots were shown. Simulation AIR-CDR lines were created to assess the effects of different diagnostic performances of prostate MRI and the prevalence of csPCa. ResultsA total of 3,207 examinations were interpreted by 33 radiologists. Overall AIR, CDR, and CDR adjusted for pathologic confirmation rate at PI-RADS 3 to 5 (PI-RADS 4 and 5) were 51.7% (36.5%), 22.1% (18.8%), and 30.7% (24.6%), respectively. Radiologist-level AIR and CDR at PI-RADS 3 to 5 (PI-RADS 4 and 5) were in the 36.8% to 75.6% (21.9%-57.5%) range and the 16.3%-28.7% (10.9%-26.5%) range, respectively. In the simulation, changing parameters of diagnostic performance or csPCa prevalence shifted the AIR-CDR line. ConclusionsThe authors propose CDR and AIR as performance metrics in prostate MRI and report reference performance values in patients with known low-grade PCa. There was variability in radiologist-level AIR and CDR. Combined use of AIR and CDR could provide meaningful feedback for radiologists to improve their performance by showing relative performance to other radiologists.

Treatment of Recurrent Low-grade Serous Ovarian Cancer With MEK Inhibitors: A Systematic Review.

Low-grade serous ovarian cancer (LGSC) represents 5% of all epithelial ovarian cancers. They are characterized by indolent growth and KRAS and BRAF mutations, differing from high-grade serous ovarian cancer both clinically and molecularly. LGSC has low response rates to traditional systemic therapies, including chemotherapy and hormonal therapy. The objective of this systematic review was to appraise the literature describing the efficacy of MEK inhibitors in the treatment of LGSC. A comprehensive search was conducted of the following databases: Medline ALL, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Sciences, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICFRP), and International Standard Randomized Controlled Trials Number (ISRCTN) Registry. All studies investigating MEKi in the treatment of LGSC in the adjuvant or recurrent setting for patients 18 years of age or older were included. All titles/abstracts were then screened by 2 independent reviewers (A.K. and C.C.). The full-text articles were then screened. All disagreements were resolved by a third independent reviewer (T.Z.). Two independent reviewers (A.K. and C.C.) extracted data from the studies deemed eligible for final review. A total of 2108 studies were identified in the initial search. Of these, a total of 4 studies met the eligibility criteria for systematic review. In these studies, 416 patients were treated with an MEKi alone. All patients included in the studies were being treated for LGSC in the recurrent setting. Varied results and efficacy of the MEKi were reported in each study. The results highlighted in this systematic review demonstrate varied responses to MEKi for recurrent LGSC. Further research is needed in this field comparing the efficacy to current therapies, as well as to further evaluate the safety and toxicity profile with long-term use of MEKi.

Single-Dose Post-Office Fulguration Mitomycin C Instillation Appears to Improve Recurrence-Free Survival in Patients With Low-Grade Noninvasive Bladder Cancer.

Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. A retrospective analysis of medical records of patients with recurrent small-volume (≤1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P=.038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR=0.552, 95% CI 0.320-0.955, P=.034) and multifocality was associated with shorter RFS (OR=1.866, 1.078-3.229, P=.026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P=.048). No complications grade 3 or higher were observed. A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications.

796P Initial management and long-term outcome of advanced low-grade serous ovarian cancer (LGSOC) exploring role of surgery and maintenance therapy in the French multicentre ESME database

796P Initial management and long-term outcome of advanced low-grade serous ovarian cancer (LGSOC) exploring role of surgery and maintenance therapy in the French multicentre ESME database

SUMO-Activating Enzyme Subunit 1 Is Associated with Poor Prognosis, Tumor Progression, and Radio-Resistance in Colorectal Cancer.

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period of about five weeks prior to surgery. Radical resection of the tumor is performed at least six to eight weeks after concurrent chemoradiotherapy (CCRT). However, this approach fails to produce the desired therapeutic effect in approximately 20% to 30% of patients, and such patients are unnecessarily exposed to the risks of radiation and drug toxicity posed by this therapy. Therefore, it is crucial to explore new biomarkers to predict the prognosis of CRC. SUMO-activating enzyme subunit 1 (SAE1) plays an important role in SUMOylation, a post-translational modification involved in cellular functions, such as cell proliferation, cell cycle, and apoptosis. In our study, to explore the clinical-pathological role of SAE1 protein in CRC, we evaluated the clinical data and paraffin sections from CRC patients. The expression of SAE1 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan-Meier survival tests. The results of in vitro proliferation and radiosensitive assays were compared between control groups and SAE1 siRNA groups. Western blotting was also used to detect the expressions of the SAE1, PARP, cyclin D1, p-NF-κB, and NF-κB proteins. Flow cytometry and colony formation assays were used to detect the effect of SAE-1 on radiosensitivity. In vivo, we detected the growth curve in a mouse xenograft model. The results showed that SAE-1 was revealed to be an independent prognostic biomarker of CRC. SAE1 knockdown inhibited CRC proliferation in vitro and in vivo, and led to the cleavage of PARP, downregulation of cyclin D1 protein expression, and downregulation of p-NF-κB/NF-κB. Additionally, SAE1 knockdown promoted radiosensitivity in CRC cells. Therefore, it was inferred that SAE1 may be used as a potential therapeutic target in CRC treatment.

Impact of reactive changes on multigene testing: histopathologic analysis of low-grade breast cancers with high-risk 21-gene recurrence scores.

The 21-gene recurrence score (RS) assay predicts the recurrence risk and magnitude of chemotherapy benefit in patients with invasive breast cancer (BC). This study examined low-grade tumors yielding a high-risk RS and their outcomes.Kindly check the edit made in the article titleOk METHODS: We compared patients with grade 1 BC and a high-risk RS to those with low-risk RS. Histologic sections were reviewed and features reported to elevate the RS were noted, mainly biopsy cavity and reactive stromal changes (BXC). A total of 54 patients had high-risk RS (median RS of 28, range 26-36). On review, BXC were seen in all cases. Thirty BCs in this group also had low to negative PR. Treatment regimens included: chemoendocrine therapy (63%), endocrine therapy alone (31%) and no adjuvant therapy (6%). There were no additional breast cancer events over a median follow-up of 54.0 months (range 6.2 to 145.3). A total of 108 patients had low-risk RS (median RS of 7, range 0-9). BXC were seen in 47% of cases and none were PR negative. One patient had a recurrence at 64.8 months while the rest had no additional events over a median of 68.1 months (2.4 to 100). We provide further evidence that reactive stromal changes and/or low-PR scores enhance the elevation of the RS. A high-RS result in low grade, PR-positive BC may not reflect actual risk and any suspected discrepancies should be discussed with the management teams. Multigene testing results should be interpreted after correlation with pathologic findings to optimize patient care.