High-risk Pathologic Features Research Articles

Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma

Adjuvant therapy is an important and effective treatment for retinoblastoma. However, there is a lack of head-to-head clinical trials comparing 3 vs 6 cycles of CEV chemotherapy (carboplatin, etoposide, and vincristine) for enucleated unilateral retinoblastoma with high-risk pathological features. To assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features. This double-center, randomized, open-label, noninferiority trial was conducted at 2 premier eye centers in China and included 187 patients who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration) between August 2013 and March 2024. The final date of follow-up was March 21, 2024. Patients were randomly assigned to receive either 3 (n = 94) or 6 (n = 93) cycles of CEV chemotherapy regimen after enucleation. The primary end point was disease-free survival, with a noninferiority margin of 12%. Secondary end points encompassed overall survival, safety, economic burden, and the quality of life of children. All 187 patients (median [IQR] age, 25.0 [20.0-37.0] months; 83 [44.4%] female) completed the trial. Median (IQR) follow-up was 79.0 (65.5-102.5) months. Five-year disease-free survival was 90.4% for the 3-cycle group vs 89.2% for the 6-cycle group (difference, 1.2% [95% CI, -7.5% to 9.8%]), which met the noninferiority criterion (P = .003 for noninferiority). The 6-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life scores, and increased costs compared with the 3-cycle group. Among patients with unilateral pathologic high-risk retinoblastoma, 3 cycles of CEV chemotherapy resulted in 5-year disease-free survival that was noninferior to 6 cycles of CEV chemotherapy. ClinicalTrials.gov Identifier: NCT01906814.

Postoperative radiotherapy with docetaxel versus cisplatin for high-risk oral squamous cell carcinoma: a randomized phase II trial with exploratory analysis of ITGB1 as a potential predictive biomarker

BackgroundOral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT).MethodsIn this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III–IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin β1 (ITGB1) expression was analyzed as a biomarker for efficacy.ResultsAfter a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT.ConclusionsThis randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting.Trial registrationwww.ClinicalTrials.gov. NCT02923258 (date of registration: October 4, 2016)

Abstract PO3-13-09: Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes

Abstract Background: Molecular residual disease (MRD) describes detectable circulating tumor DNA (ctDNA) after definitive surgery and is an expanding field in breast oncology. Multiple studies have demonstrated detectable MRD to be poorly prognostic, and clinical trials are now underway assessing the efficacy of therapeutic interception. However, most retrospective studies did not obtain baseline imaging at the time of MRD detection, such that the proportion of patients with detectable ctDNA and concurrent radiographically evident recurrent disease is not known. Furthermore, the role of serial ctDNA testing in the adjuvant setting remains unclear. Meanwhile, tumor-informed assays such as the SignateraTM platform are now covered by Medicare. To address these outstanding clinical questions, we aimed to determine the temporal dynamics of MRD detection in HR+/HER2- breast cancer, association with radiographic recurrence, and impact on clinical outcomes. Methods: Patients with HR+/HER2- breast cancer who underwent MRD testing either as part of a clinical trial or via an expanded access program were reviewed for MRD positivity and assessed alongside clinically annotated data. All patients completed surgical resection prior to MRD testing. Whole exome sequencing of primary tumor tissue and personalized ctDNA primers were designed for multiplex PCR targeting up to 16 single nucleotide variants for MRD testing via the SignateraTM platform. Clinical data was determined through focused chart review. Results: Among 185 patients with HR+/HER2- breast cancer who underwent MRD testing, 37 patients (20%) did not complete testing due to factors including tumor tissue not meeting pathology parameters, insufficient quantity of primary tissue, or tumor/normal discordance. 14 patients (8%) had detectable ctDNA (1, 5, and 8 patients had stage I, II, and III breast cancer, respectively). Among the 6 patients who did not have stage III disease, 3 had other high-risk features (Oncotype 40; grade 3 disease x2). Overall, 71% (n=10) of the +MRD population tested positive at the first test, while 29% (n=4) tested positive only on serial sampling. Median time from surgery to positive test was 3.5 years (range: 1 month – 10.2 years). Twelve patients (86%) were on adjuvant endocrine therapy at the time of detectable MRD. Among the 14 +MRD patients, 9 underwent staging scans shortly after positive MRD testing, and among these patients, 3 (33%) had radiographic evidence of asymptomatic metastatic recurrence (2 bone-only; 1 visceral); two of these pts had 1 MRD test, while the other had a negative test followed by a positive test 11 months later. The other 3 patients with radiographic recurrences had scans prompted only by clinical symptoms >6 months after +MRD. Among the 4 patients with serial data after first +MRD testing, none experienced subsequent ctDNA clearance. Serial testing occurred over a median of 11.5 months (range 1.1-21.7 months). With median follow up of 8.6 months, 43% (n=6) of patients with +MRD had distant disease recurrence. Conclusions: Personalized tumor-informed ctDNA testing identified patients with high risk of recurrence, including patients without classic high-risk clinical, pathologic, or genomic features, suggesting a complementary role of MRD testing for risk assessment. Serial monitoring was necessary to identify MRD in more than a quarter of patients. Furthermore, one-third of patients with +MRD disease had asymptomatic metastatic recurrence, highlighting the importance of staging scans in studies and clinical trials assessing therapeutic interception in the adjuvant setting. Citation Format: Arielle Medford, Elyssa Denault, Zanta Ephrem, Douglas Micalizzi, Yael Bar, Rachel Abelman, Amy Comander, Justine Knape, Minetta Liu, Angel Rodriguez, Steven Isakoff, Beverly Moy, Laura Spring, Aditya Bardia. Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-09.

Molecular and pathologic data to guide selection of patients with endometrioid endometrial cancer for ovarian preservation

ObjectivesTo investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer.MethodsPatients with endometrial cancer ≤50 years of age...

Variation in management of lymph node positive prostate cancer after radical prostatectomy within a statewide quality improvement consortium

BackgroundPatients with lymph node positive (pN+) disease found at the time of radical prostatectomy with pelvic lymphadenectomy for clinically localized prostate cancer (CaP) are at high risk of disease persistence and progression. Contemporary management trends of pN+ CaP are not well described. Materials and methodsPatients in the Michigan Urologic Surgery Improvement Collaborative (MUSIC) with clinically localized prostate cancer who underwent radical prostatectomy between 2012 and 2023 with cN0/pN+ disease were identified. The primary outcome was to evaluate patient and practice-level factors associated with time to secondary post-RP treatment. Secondary outcomes included practice-level variation in management of pN+ CaP and rates of secondary treatment modality. To assess factors associated with secondary treatment, a Cox proportional hazards model of a 60-day landmark analysis was performed. ResultsWe identified 666 patients with pN+ disease. Overall, 66% underwent secondary treatment within 12 months post-RP. About 19% of patients with detectable post-RP PSA did not receive treatment. Of patients receiving secondary treatment after 60-days post-RP, 34% received androgen deprivation therapy (ADT) alone, 27% received radiation (RT) alone, 36% received combination, and 4% received other systemic therapies. In the multivariable model, pathologic grade group (GG)3 (HR 1.5; 95%CI: 1.05–2.14), GG4-5 (HR 1.65; 95%CI: 1.16–2.34), positive margins (HR 1.46; 95%CI: 1.13–1.88), and detectable postoperative PSA ≥0.1 ng/ml (HR 3.46; 95%CI: 2.61–4.59) were significantly associated with secondary post-RP treatment. There was wide variation in adjusted practice-level 12-month secondary treatment utilization (28%–79%). ConclusionsThe majority pN+ patients receive treatment within 12 months post-RP which was associated with high-risk pathological features and post-RP PSA. Variation in management of pN+ disease highlights the uncertainty regarding the optimal management. Understanding which patients will benefit from secondary treatment, and which type, will be critical to minimize variation in care.

Abstract 961: Detection of minimal residual disease in lymph predicts recurrence in HPV-negative head and neck cancer patients

Abstract Background: Locoregional cancer relapse remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC), particularly for HPV-negative patients whose 2-year locoregional failure rate is up to 50%. There is unmet need for an accurate diagnostic test that predicts risk of recurrence prior to adjuvant therapy selection. We present a novel proximal assay for minimal residual disease (MRD) profiled in lymphatic exudate collected via surgical drains (“lymph”). Methods: Lymph, plasma, and blood were collected from 46 HPV-negative HNSCC patients postoperatively at 24 hours along with resected tumor. Cell-free DNA was extracted from lymph and plasma and sequenced using the TruSeq Oncology 500 panel to a depth of >100 million reads. Somatic mutations were identified by exome sequencing (200x) tumor and blood. Five patients had <2 mutations in tumor and were excluded. Two patients were censored due to lack of clinical data, yielding 18 patients with disease recurrence (REC) and 21 with no evidence of disease (NED) with >1 year of follow-up. Tumor-specific variants were force-called in lymph and plasma using a custom pipeline. Patients were considered MRD positive if the mean variant allele fraction (mVAF) was greater than 0.015% (the estimated limit of detection). The Kaplan-Meier (KM) estimator with log-rank test and Cox proportional-hazards model were used for survival analyses. Logistic regression model was performed with 5-fold cross-validation. Results: KM survival analyses showed lymph accurately predicts recurrence (sensitivity (SN) = 78%, specificity (SP) = 67%; p = 0.003, Hazard ratio (HR) = 4.7), while plasma was not significant (p = 0.92) at this postoperative timepoint. Performance was enhanced for locoregional relapse (SN = 92%, SP = 67%; p = 0.001, HR = 13.9. N=33). We also observed accurate recurrence prediction (SN = 83%, SP = 69%, p = 0.03, HR = 7.7) in the 19 N0 patients (node-negative by pathology). Lymph MRD outperformed individual pathology features (extranodal extension, perineural invasion, lymphovascular invasion, and nodal disease status) for recurrence prediction (HR = 3.4, 0.88, 2.5, 2.4, respectively). A logistic regression model combining lymph MRD with these 4 high-risk pathologic features showed superior performance over lymph alone or pathology alone (SN = 89%, SP = 67%; p = 0.0007, HR = 8.6). Conclusions: ctDNA analysis of lymph from surgical drains represents a novel proximal MRD approach in HPV-negative HNSCC. Postoperative lymph significantly outperforms plasma for prediction of recurrence, particularly in patients with locoregional relapse. Accurate MRD identification in patients with lower risk pathologic features suggests that lymph MRD testing has potential to augment traditional pathology and provide more personalized adjuvant treatment decision-making in patients with HPV-negative HNSCC. Citation Format: Wendy Winckler, Zhuosheng Gu, Damion Whitfield, Noah Earland, Adam Harmon, Megan Long, Peter Harris, Zhongping Xu, Ricardo Ramirez, Sophie Gerndt, Maciej Pacula, Marra S. Francis, Jose P. Zevallos, Aadel A. Chaudhuri. Detection of minimal residual disease in lymph predicts recurrence in HPV-negative head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 961.

Tumour deposits are independently associated with recurrence in colon cancer.

Tumour deposits are focal aggregates of cancer cells in pericolic fat and mesentery, distinct from vessels, nerves and lymphatics. Their presence upstages lymph node negative patients but is ignored in lymph node positive patients. We investigated the clinicopathological factors associated with tumour deposits and their impact on recurrence in lymph node positive and negative patients. Clinicopathological variables were collected from the medical records of patients with Stage I-III colon cancer who underwent resection in 2017-2019. Pathology was reviewed by a gastrointestinal pathologist. Patients with rectal cancer, metastasis, and concurrent malignancy were excluded. Tumour deposits were noted in 69 (9%) of 770 patients. They were associated with the presence of lymph node metastasis, advanced T category, poorly differentiated tumours, microsatellite stable subtype and lymphovascular and perineural invasion (p < 0.05). The presence of tumour deposits (hazard ratio 2.48, 95% CI 1.49-4.10) and of lymph node metastasis (hazard ratio 3.04, 95% CI 1.72-5.37) were independently associated with decreased time to recurrence. There was a weak correlation (0.27) between the number of tumour deposits and the number of positive lymph nodes. Tumour deposits are associated with more advanced disease and high-risk pathological features. The presence of tumour deposits and lymph node metastasis were found to be independent risk factors for decreased time to recurrence. A patient with both lymph node metastasis and tumour deposits is more than twice as likely to have recurrence compared with a patient with only lymph node metastasis. Tumour deposits independently predict recurrence and should not be ignored in lymph node positive patients.

Retinoblastoma treatment in a Brazilian population. Presentation and long-term results.

Retinoblastoma is a malignant tumor with a high cure potential when proper therapy is used. The purpose of this paper is to report the clinical features and outcomes of patients with retinoblastoma who were treated with a combination of local and systemic chemotherapy-based protocols. We retrospectively studied patients treated with systemic chemotherapy plus local treatment between 2003 and 2015 with a follow-up ≥2 years. We correlated clinical and pathological characteristics with decimal visual acuity (VA) and death. Among 119 patients, 60% had unilateral disease (UNI), and 52% were male. The median presentation age was 19.5 months, 10% had a positive family history, and the most frequent sign was leukocoria (68.8%). Advanced disease was more frequent in eyes with UNI (98.4%) than in eyes with bilateral retinoblastoma (BIL: 55.3%). Enucleation was performed in 97% of UNI eyes and in 55.8% of BIL eyes. The overall globe salvage was 26.6%, 44.25% of BIL eyes. Bilateral enucleation was required in 5%. High-risk pathologic features occurred in 50% and 37% of eyes enucleated without and with neoadjuvant chemotherapy, respectively. High-risk features were related to the presence of goniosynechiae in the pathologic specimen and were more frequent in children younger than 10 months or older than 40 months. Extraocular disease was present in 5% of patients, and the death rate related to metastasis of the tumor was 8%. The final VA was ≥ 0.7 in 72.8% and ≥0.1 in 91% of BIL patients. Treatment of retinoblastoma with conservative systemic-based chemotherapy was associated with an excellent survival rate (92%). Albeit the low overall globe salvage rate, in BIL patients, approximately half the eyes were conserved, and a satisfactory functional visual result was achieved The evaluated protocol is an important treatment option, especially in developing countries.

Interaction analysis of high-risk pathological features on adjuvant chemotherapy survival benefit in stage II colon cancer patients: a multi-center, retrospective study

BackgroundWe aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy.MethodsThis study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect.ResultsA total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54–72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282–3.660, P = 0.004; HR 1.583, 95% CI 0.985–2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725).ConclusionsPerineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study.Trial registrationThis study is registered on ClinicalTrials.gov, NCT03794193 (04/01/2019).

Abstract PR09: Detection of minimal residual disease in post-surgical drain fluid can predict locoregional recurrence in HPV-negative head and neck cancer patients

Abstract Introduction: Locoregional cancer relapse remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC), particularly for HPV-negative patients whose 3-year locoregional failure rate is 32.5%. There is a major unmet need for an accurate diagnostic test that predicts risk of locoregional recurrence prior to adjuvant therapy selection. We present a novel proximal assay for minimal residual disease (MRD) profiled in lymphatic exudate collected via surgical drains (“lymph”). Methods: Lymph, plasma, and peripheral blood were collected from 22 HPV-negative HNSCC patients postoperatively at 24 hours along with resected tumor. Cell-free DNA was extracted from lymph and plasma and sequenced using the TruSeq Oncology 500 panel to a depth of &amp;gt;100 million reads. One plasma sample failed due to inadequate coverage. Two patients were censored due to lack of clinical data, yielding 9 patients with disease recurrence (REC) and 11 with no evidence of disease (NED) with &amp;gt;1 year of follow-up. Somatic mutations were identified from exome sequencing (200x) in tumor with matched blood. Tumor-specific variants were force-called in lymph and plasma using a custom bioinformatic pipeline. Mutation calls were filtered by a base-specific error model to eliminate artifacts. Student’s t-test was used for group comparisons. The Kaplan-Meier (KM) estimator with log-rank test and Cox proportional-hazards model were used for survival analyses. Results: ctDNA allelic fraction was 1.5x higher in lymph than in plasma (lymph = 0.11% ± 0.16%; plasma = 0.076% ± 0.12%. p = 0.018, N = 100 mutations). Significantly more mutations were detected in REC lymph compared to NED (p = 0.009), but not in plasma REC vs. NED (p = 0.16). We classified patients as positive (&amp;gt;1) or negative (£1) for detected mutations in each analyte and performed a KM survival analysis, showing lymph could accurately predict recurrence (sensitivity = 89%, specificity = 82%; p &amp;lt; 0.005) while plasma could not (sensitivity = 67%, specificity = 40%; p = 0.59). The hazard ratio in lymph was 12.52 (95% CI 1.54-101.61). We stratified REC patients by locoregional or locoregional + distant relapse and observed significantly more mutations detected in lymph (p = 0.01) from locoregional relapse while lymph and plasma performed similarly for locoregional + distant relapse (p = 1.0). We compared lymph MRD outcomes to extranodal extension (ENE), a high-risk pathologic feature. Lymph was concordant with ENE in 12/20 patients and identified an additional 6 ENE-negative relapse cases. Conclusion: Postoperative ctDNA analysis of lymph from surgical drains represents a novel MRD approach in HPV-negative HNSCC. Lymph significantly outperforms plasma for prediction of recurrence, particularly in patients with locoregional relapse. Accurate MRD identification in patients with lower risk pathologic features suggests that postoperative lymph MRD testing has the potential to significantly augment traditional pathology and provide more personalized adjuvant treatment decision-making in patients with HPV-negative HNSCC. Citation Format: Aadel A. Chaudhuri, Zhuosheng Gu, Damion Whitfield, Noah Earland, Adam Harmon, Megan Long, Peter Harris, Zhongping Xu, Ricardo Ramirez, Sophie Gerndt, Maciej Pacula, Marra S. Francis, Wendy Winckler, Jose P. Zevallos. Detection of minimal residual disease in post-surgical drain fluid can predict locoregional recurrence in HPV-negative head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR09.

Abstract PO-066: Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer

Abstract Introduction: Locoregionally advanced p16+ squamous cell carcinoma of the oropharynx (OPSCC) is most often treated either with primary chemoradiation (CRT) or surgery followed by adjuvant treatment. Surgery alone is often insufficient treatment as adverse features such as extranodal extension, close or positive margins, lymphovascular invasion, or multiple positive lymph nodes are often identified, resulting in the need for adjuvant radiation or CRT. Primary surgery is often not pursued in more advanced cases since surgical pathology may show adverse features requiring adjuvant CRT, resulting in "triple therapy", the effects of which may worsen risk of long-term treatment toxicity. Our institution has demonstrated excellent oncologic and quality of life outcomes using a neoadjuvant chemotherapy (NAC) regimen of cisplatin and docetaxel prior to surgical treatment with TORS and neck dissection. Due to high rates of clinical-to-pathologic downstaging, adjuvant treatment is often avoided entirely. Here, we explore whether the development of a complete pathologic (pCR) response following NAC associates with 2-year recurrence free survival. Methods: A retrospective cohort study of patients receiving neoadjuvant doublet cisplatin and docetaxel followed by surgery (NAC+S) at a single institution between October 2015 and March 2023 was performed and pathologic responses and 2-year recurrence free survival was recorded following IRB exemption. Results: Fifty-four patients with p16+ OPSCC treated with NAC+S were identified. 49 patients (91%) received three cycles of NAC; 5 patients (9%) received two cycles. Comparing clinical staging to pathologic analysis of surgical specimens, 40 of 54 patients (68%) experienced clinical-to-pathologic downstaging after NAC. A pCR was identified in 23 of 54 patients (43%). Of patients that did not develop a pCR, 9 of 31 patients (29%) received adjuvant treatment due to the identification of high-risk pathologic features. Of patients that developed a pCR, 1 of 23 (4%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did not require adjuvant treatment, 2 of 22 (9%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did require adjuvant treatment, 2 of 9 (22%) developed disease relapse within 2 years. A trend toward reduced risk of disease relapse was observed in patients that develop a pCR following NAC compared to those that do not but did not reach statistical significance (1 of 23 relapses with pCR, 4 of 31 relapses without pCR; P&amp;gt;0.05, two-sided Chi-square test). Conclusion: High rates of pCR following NAC were observed in this small retrospective cohort of patients with newly diagnosed p16+ OPSCC despite 84% of patients avoiding any adjuvant treatment. Patients that develop a pCR after NAC trend toward reduced risk of recurrence compared to those that do not. The development of pCR after NAC may be a suitable short-term clinical outcome measure in prospective clinical trials of NAC for patients with newly diagnosed p16+ OPSCC. Citation Format: Alisha R. Pershad, Maxwell Madani, Timothy B. Shaver, Arjun Joshi, Clint T. Allen, Joseph F. Goodman. Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-066.

Causes of death and survival analysis for patients with retinoblastoma in Jordan.

To analyze causes and prognostic factors for death among Retinoblastoma (Rb) patients treated at a single specialized tertiary cancer center in Jordan. We reviewed the mortality causes for all Rb patients who have been treated at the King Hussein Cancer Center between 2003 and 2019 and were followed for at least 3 years after diagnosis. The main outcome measures included demographics, laterality, tumor stage, treatment modalities, metastasis, survival, and causes of death. Twenty-four (5%) of the 478 patients died from retinoblastoma and 5-year survival was 94%. The mean age at diagnosis was 15 months (median, 18 months; range, 4-38 months); eight (33%) received diagnoses within the first year of life. Eleven (46%) were boys, 16 (67%) had bilateral disease, and 3 (13%) had a positive family history. The stage for the worst eye was C for 1 (4%) patient, D in 6 (25%) patients, and E (T3) in 15 (63%) patients. Two patients had extraocular Rb at diagnosis, and four of the patients who had intraocular Rb at diagnosis refused treatment and then came back with extraocular Rb. In total, extraocular disease was encountered in six eyes (six patients). After a 120-month median follow-up period, 24 patients (5%) died of second neoplasms (n = 3) or metastases (n = 21). Significant predictive factors for metastasis and death included advanced IIRC tumor stage (p < 0.0001), the presence of high-risk pathological features in the enucleated eyes (p = 0.013), parental refusal of the recommended primary treatment plan (p < 0.0001), and extraocular extension (p < 0.0001). The 5-year survival rates of Rb patients in Jordan are as high as those in high-income countries. However, 5% are still dying from metastatic disease, prompting the need for awareness campaigns to educate the public about the high cure rates and to prevent treatment abandonment.

Development and validation of a prognostic prediction model for patients with stage Ⅰ to Ⅲ colon cancer incorporating high-risk pathological features

Objective: To examine a predictive model that incorporating high risk pathological factors for the prognosis of stage Ⅰ to Ⅲ colon cancer. Methods: This study retrospectively collected clinicopathological information and survival outcomes of stage Ⅰ~Ⅲ colon cancer patients who underwent curative surgery in 7 tertiary hospitals in China from January 1, 2016 to December 31, 2017. A total of 1 650 patients were enrolled, aged (M(IQR)) 62 (18) years (range: 14 to 100). There were 963 males and 687 females. The median follow-up period was 51 months. The Cox proportional hazardous regression model was utilized to select high-risk pathological factors, establish the nomogram and scoring system. The Bootstrap resampling method was utilized for internal validation of the model, the concordance index (C-index) was used to assess discrimination and calibration curves were presented to assess model calibration. The Kaplan-Meier method was used to plot survival curves after risk grouping, and Cox regression was used to compare disease-free survival between subgroups. Results: Age (HR=1.020, 95%CI: 1.008 to 1.033, P=0.001), T stage (T3:HR=1.995,95%CI:1.062 to 3.750,P=0.032;T4:HR=4.196, 95%CI: 2.188 to 8.045, P<0.01), N stage (N1: HR=1.834, 95%CI: 1.307 to 2.574, P<0.01; N2: HR=3.970, 95%CI: 2.724 to 5.787, P<0.01) and number of lymph nodes examined (≥36: HR=0.438, 95%CI: 0.242 to 0.790, P=0.006) were independently associated with disease-free survival. The C-index of the scoring model (model 1) based on age, T stage, N stage, and dichotomous variables of the lymph nodes examined (<12 and ≥12) was 0.723, and the C-index of the scoring model (model 2) based on age, T stage, N stage, and multi-categorical variables of the lymph nodes examined (<12, 12 to <24, 24 to <36, and ≥36) was 0.726. A scoring system was established based on age, T stage, N stage, and multi-categorical variables of lymph nodes examined, the 3-year DFS of the low-risk (≤1), middle-risk (2 to 4) and high-risk (≥5) group were 96.3% (n=711), 89.0% (n=626) and 71.4% (n=313), respectively. Statistically significant difference was observed among groups (P<0.01). Conclusions: The number of lymph nodes examined was an independent prognostic factor for disease-free survival after curative surgery in patients with stage Ⅰ to Ⅲ colon cancer. Incorporating the number of lymph nodes examined as a multi-categorical variable into the T and N staging system could improve prognostic predictive validity.

More attention for high-risk pathological features for stage Ⅱ colorectal cancer required

Stage Ⅱ (T3-4N0M0) accounts for 25% of colorectal cancer and five-year survival is between 70% and 80%. However, 25% of patients develop distant metastases and have a survival rate similar to that of stage Ⅲ disease. However, whether or not to give adjuvant chemotherapy is still a controversial issue. As a result, there has been a lot of interest in the identification of the pathological factors underlying the poor prognosis associated with this stage, in order to establish a firmer basis for the administration of adjuvant chemotherapy. But not all high-risk factors are equal for stage Ⅱ colorectal cancer, variability still exists in the management and outcomes of high-risk patients. Here be introduced and commented on thinking and understanding about its controversy and evolution for the attention of the working pathologist and gastroenterologist doctors.

Reevaluating the role of adjuvant chemotherapy in early-stage, resectable NSCLC with high-risk clinical and pathologic features.

8572 Background: The preferred treatment for early-stage non-small cell lung cancer remains surgical resection with the consideration of adjuvant chemotherapy for tumors with certain high-risk features. It is commonly cited that such treatments confer a meager 5% 5-year survival benefit compared to observation alone. We sought to reassess the benefit of adjuvant chemotherapy using modern, real-world datasets. Methods: We performed a retrospective cohort study using a dataset from the National Cancer Database. All patients with early-stage stage NSCLC (3-5cm, node-negative) who would be eligible for adjuvant chemotherapy based on National Comprehensive Cancer Network guidelines were included (i.e., presence of at least 1 high-risk feature). High-risk clinical and pathologic features were defined as poor differentiation, tumor size (≥4cm), non-anatomic wedge resection, inadequate lymph node evaluation, vascular invasion, and visceral pleural involvement. We employed average treatment effect on the treated (ATT) weighting to match patients with similar demographic, tumor, and treatment-related variables to compare outcomes between chemotherapy versus observation groups. The primary outcome was overall survival. These findings were further validated in an independent cohort from the US Veteran Health Administration (VHA). Results: The study included 10,812 patients with early-stage NSCLC who had at least 1 high-risk feature. The frequencies of high-risk features were as follows: tumor size ≥4cm (n = 3,271, 30.3%), poor differentiation (n = 9,454, 87.4%), visceral-pleural invasion (n = 2,542, 23.5%), vascular invasion (n = 1,742, 16.11%), non-anatomic wedge resection (n = 781, 7.2%), and inadequate nodal sampling (n = 6,306, 58.3%). Despite the presence of high-risk features, only 1,427 (13.2%) patients received adjuvant chemotherapy. In the ATT weighted analysis, 1,261 (49.7%) patients received adjuvant chemotherapy and 1,278 (50.3%) patients received observation. The 5-year overall survival was 70.0% (95% CI 67.1-72.7) in the chemotherapy group versus 62.0% (95% CI 60.2-63.7%) in the observation group (absolute 5-year survival difference 8.0%). In the VHA cohort, 11.3% of patients received adjuvant chemotherapy. Similarly, the 5-year overall survival was 64.0% (95% CI 51.4-74.2) in the chemotherapy group versus 56.2% (95% CI 48.3-63.4) in the observation group (absolute 5-year survival difference 7.8%). Conclusions: These data suggest a notably larger benefit of adjuvant chemotherapy in eligible patients with high-risk clinical pathologic features compared to commonly cited statistics. With the addition of more robust treatment options in early-stage disease, adherence to adjuvant and neoadjuvant treatment guidelines may disproportionately improve early-stage NSCLC outcomes following curative-intent resection.

Abstract 734: Comprehensive validation of high-risk clinicopathologic features in early-stage, node-negative non-small cell lung cancer

Abstract Objective: Current guidelines recommend adjuvant therapy for patients with completely resected non-small cell lung cancer (NSCLC) with high-risk clinical or pathologic features. Despite this, the relationship between these features and cancer recurrence is poorly elucidated. Methods: We conducted a retrospective cohort study using a uniquely compiled dataset from the US Veterans Health Administration (VHA) including all Veterans with pathologic early-stage (≤5cm, N0) NSCLC receiving definitive surgical treatment (2010-2016). Based on National Comprehensive Cancer Network guidelines, we evaluated 6 high-risk features: tumor size, tumor grade, visceral-pleural invasion, lymphovascular invasion, non-anatomic wedge resection, and adequacy of nodal sampling. We developed a score reflecting the relationship between these high-risk features and recurrence, using a multivariable competing risk model (death as competing event). The score performance was then tested in an external cohort from the National Cancer Database (NCDB). Results: The study included 3,799 Veterans. The median follow-up was 7.1 years. Recurrence was detected in 800 (21.1%) patients. The association between high-risk features and cancer recurrence were as follows: tumor size (e.g., 31-40mm vs. 0-10mm, multivariable-adjusted hazard ratio, aHR 1.676, 95% CI 1.229-2.285, p=0.001), tumor grade (e.g., III vs. I, aHR 1.884, 95% CI 1.448-2.449, p&amp;lt;0.001), visceral-pleural invasion (aHR 1.096, 95% CI 0.905-1.329, p=0.35), lymphovascular invasion (aHR 1.747, 95% CI 1.441-2.117, p&amp;lt;0.001), non-anatomic wedge resection (aHR 1.335, 95% CI 1.101-1.619, p=0.003), and adequacy of nodal sampling (e.g., 1-4 lymph nodes vs. ≥10 lymph nodes, aHR 1.392, 95% CI 1.149-1.687, p&amp;lt;0.001). Using these parameters, a score was created reflecting the association between high-risk features and recurrence. The score ranged from 0-36, with higher scores reflecting higher cumulative incidence of recurrence. The score was further divided into low- (0-11, n=1,263, 33.3%; 5-yr recurrence risk 13.0%), moderate- (12-15, n=1,134, 29.9%; 5-yr recurrence risk 19.0%), and high-risk (16-36, n=1,402, 36.9%; 5-yr recurrence risk 27.1%) categories. Higher scores were also associated with diminished overall survival (median OS, low-risk: 9.0 yrs; moderate-risk: 7.3 yrs; high-risk: 5.4 yrs). The score was further tested in a cohort of 63,232 patients from the NCDB and higher scores remained associated with worse overall survival (median OS, low-risk: 9.4 yrs; moderate-risk: 8.0 yrs; high-risk: 6.3 yrs). Conclusions: High-risk clinicopathologic features are associated with dramatically higher risk of recurrence and worse overall survival. Multivariable assessment of these features using a comprehensive yet pragmatic score may help to standardize adjuvant treatment eligibility following curative intent resection. Citation Format: Brendan T. Heiden, Daniel B. Eaton, Su-Hsin Chang, Yan Yan, Martin W. Schoen, Bindiya G. Patel, Theodore S. Thomas, Bryan F. Meyers, Benjamin D. Kozower, Varun Puri. Comprehensive validation of high-risk clinicopathologic features in early-stage, node-negative non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 734.

A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.

TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 .

Update on Prognostic and Predictive Markers in Mucinous Ovarian Cancer

This review includes state-of-the-art prognostic and predictive factors of mucinous ovarian cancer (MOC), a rare tumor. Clinical, pathological, and molecular features and treatment options according to prognosis are comprehensively discussed. Different clinical implications of MOC are described according to the The International Federation of Gynecology and Obstetrics (FIGO) stage: early MOC (stage I-II) and advanced MOC (stage III-IV). Early MOC is characterized by a good prognosis. Surgery is the mainstay of treatment. Fertility-sparing surgery could be performed in patients who wish to become pregnant and that present low recurrence risk of disease. Adjuvant chemotherapy is not recommended, except in patients with high-risk clinical and pathological features. Regarding the histological features, an infiltrative growth pattern is the major prognostic factor of MOC. Furthermore, novel molecular biomarkers are emerging for tailored management of early-stage MOC. In contrast, advanced MOC is characterized by poor survival. Radical surgery is the cornerstone of treatment and adjuvant chemotherapy is recommended, although the efficacy is limited by the intrinsic chemoresistance of these tumors. Several molecular hallmarks of advanced MOC have been described in recent years (e.g., HER2 amplification, distinct methylation profiles, peculiar immunological microenvironment), but target therapy for these rare tumors is not available yet.

A comparison of high risk pathological features between primary and secondary enucleation for retinoblastoma.

To compare the risk and pattern of High-Risk Pathologic Features (HRPF) in retinoblastoma between primary and secondary enucleation. A retrospective analysis of 121 eyes from 118 patients who underwent enucleation at the King Hussein Cancer Center (KHCC) Amman, Jordan, between November 2009 and January 2020. Demographic information, tumor stage, time from diagnosis-to-enucleation, results of pathology, metastasis, and mortality were retrieved. Patients in the secondary group (49/121 eyes, 40%) were considerably younger at diagnosis (p = 0.0014), had bilateral disease (p = 0.0001), and had less-progressed disease at presentation (p = 0.016) compared to the primary enucleation. Primarily enucleated eyes were more-likely to have massive choroidal invasion (p = 0.0315) and post-laminar optic nerve invasion (p = 0.027), in spite of the finding that the overall prevalence of HRPF was similar between the two groups (35.5 percent vs. 37.5 percent; p = 0.585). The likelihood of anterior chamber invasion, was considerably higher in secondary enucleated eyes (p = 0.013). We evaluated primary and secondary enucleation for each subgroup (D and E) of the International Intraocular Retinoblastoma Classification (IIRC) and found the prevalence of HRPF was comparable (p = 0.58, 1.0, respectively). The difference in time between diagnosis-to-enucleation in secondary enucleation did not predict HRPF (p = 0.50). There was no discernible difference between primary and secondary enucleated eyes in terms of metastasis or survival (p = 0.156 and 0.44, respectively). Systemic chemotherapy has the ability to reduce the extent of tumor expansion that has been pathologically identified. Primary and secondary enucleated eyes are comparable in low metastatic risk only when strict examination and management guidelines are followed.

Pathological features associated with lymph node disease in patients with appendiceal neuroendocrine tumors.

238 Background: Appendiceal neuroendocrine tumors (ANETs) are well known for their benign and slow progression; nonetheless, the presence of lymph node metastasis has been described in up to 50% of all cases. The risk of metastasis is mainly associated with tumor size, and the role of other pathological features remains unclear. Hence, this study was designed to assess the pathologic features of ANETs associated with an increased risk of lymph node metastasis. Methods: Patients ≥18yrs of age with ANETs were identified in the National Cancer Database (NCDB) from 2004 to 2017. Groups were defined based on lymph node status as N(-) (all examined nodes were negative) and N(+) (one or more examined nodes were positive). Multivariable models using demographics and oncological features were used to identify factors independently associated with nodal metastasis (N+). Marginal effects, specifically for tumors &lt;2 cm were also calculated. Results: A total of 2,465 cases were identified and included for data analysis. Among these, 23% had lymph node metastases, including 33 of 979 tumors &lt;1 cm (3.4%), and 145 of 696 tumors ≥1 cm but ≤2 cm (20.8%). Tumor size, depth of tumor invasion, and presence of lymphovascular invasion (LVI) were identified as independent predictors of lymph node metastasis (p &lt;0.001). When evaluating marginal effects, both the depth of tumor invasion and the presence of LVI were associated with increased risk of node metastasis in small tumors (&lt;2 cm), comparable to the mere risk of node metastasis in big tumors (≥2cm). In addition, for small ANETs (&lt;2cm), the true positive rates (TPR) of node metastasis vary according to the number of assessed lymph nodes, differing significantly between patients with at least 12 evaluated lymph nodes vs. those with less than 12 (TPR 4.7% vs. 1.6% for &lt;1 cm [p =0.02], and 40.1% vs. 25.7% in ≤2 cm ANETs, [p &lt;0.001]). Conclusions: In ANETs, the presence of high-risk pathological features, including LVI and tumor depth, increases the risk of node metastasis in addition to tumor size, and should be considered when selecting the optimum management and follow-up in these patients. [Table: see text]