T4 Disease Research Articles

Perioperative Outcomes of Open Extra-peritoneal Versus Laparoscopic Radical Cystoprostatectomy: A single Center Comparative Study.

To compare 90-day perioperative complications and pathological outcomes between laparoscopic radical cystectomy (LRC) and extraperitoneal radical cystectomy (EORC) approaches. All operations were performed in a single high-volume tertiary referee center by the same surgical team.Males ≥ 18 years with pre-cystectomy clinical T1-T3 disease and having undergone an ileal conduit were included. Exclusion criteria included patients with inflammatory bowel disease, previous pelvic and/or abdominal irradiation, neo-adjuvant chemotherapy, and/or clinical T4 disease. Perioperative outcomes such as operative time, estimated blood loss, transfusion rate, hospital stay, and 90-day complications were evaluated. The recovery duration of regular bowel activity, mean stool passage,and ileus rates were recorded. A total of 221 patients met the inclusion criteria(81 LRC and 130 EORC). Demographics and preoperative parameters were comparable. Intraoperative estimated blood lossfavored LRC by a median of 450 mL (200-900) P=.021) vs. a median of 700 mL (300-2900) for EORC. The transfusion rate did not differ between the two groups; %14.8 (N=12) for the LRC and %20.8 (N=27) for EORC (P=.37). The median hospital stay was 9 (4-49) days for EORC and 8 (4-29) days for LRC (P=.011). The need for analgesics to control pain through an epidural catheter was higher for EORC (P=.042). There was no difference in overall complication rates (P=.47). Although LRC appears to have a slight advantage over EORC, both techniques yield satisfactory results in regard to ileus rates and 90-day perioperative complications.

Abstract PO4-15-12: Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer

Abstract Introduction Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response in patients with breast cancer (BC). In this study, we evaluated whether serial ctDNA testing during neoadjuvant therapy (NAT) can provide an early indication of treatment response or resistance and disease progression. Methods In this real world study, longitudinal blood samples collected from 159 patients with stage I-III BC were analyzed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). Of the 159 patients, 157 received standard of care NAT; the remaining 2 patients were treated with endocrine therapy only in the neoadjuvant setting. Blood samples were collected at the time of diagnosis from 71 patients (baseline) and longitudinally during treatment from 159 patients (median time between time points: 1.5 months). ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes available at the time of data cut off. Results At baseline, ctDNA was detected in 72% (51/71) of patients. Baseline ctDNA detection rates varied based on histologic subtypes: 82% (28/34) in patients with triple negative breast cancer, 88% (15/17) in patients with HER2+ disease and 40% (8/20) in patients with ER+HER2- BC. ctDNA was detectable at baseline in 72% (26/36) of patients with clinical T1-2 disease and 92% (11/12) of patients with T3-4 disease. ctDNA was detected in 64% (16/25) of patients with clinical N0, whereas among patients with at least one positive lymph node, ctDNA was detected in 92% (22/24). At baseline, 65% (31/48) of patients with low/intermediate-grade disease were ctDNA-positive, while 81% (25/31) of patients with high-grade disease were ctDNA-positive. Similarly, 83% (24/29) of patients with high levels (>20%) of Ki67 expression had detectable ctDNA prior to treatment initiation, while only 22% (2/9) of those with low level (< 20%) of Ki67 expression had ctDNA detected. Surgical outcomes were available for 22 patients of whom 16 had achieved pathologic complete response (pCR). While 3/16 pts were ctDNA negative at baseline, all of the remaining cases except one patient with baseline ctDNA detection and serial measurements (11/12) became ctDNA negative by the end of two months of treatment. Despite achieving pCR, one patient with inflammatory ER+HER2+ BC remained ctDNA positive before and after the surgery, which informed a change in the adjuvant treatment strategy. Among those with residual disease (pT1c-T3), 28% (7/25) remained ctDNA positive after two months of NAT. Association between ctDNA dynamics and surgical outcomes of the remaining 137 patients will be presented at the time of the conference. Conclusions This real world study demonstrates the prevalence of ctDNA detection and dynamics in patients with eBC treated with NAT. ctDNA monitoring during NAT can facilitate real-time assessment of treatment response and serve as an early indicator of subsequent pCR to NAT. Citation Format: Mridula George, Trishala Meghal, Coral Omene, Ekaterina Kalashnikova, Janie Fielder, Nisha Ohri, Shicha Kumar, Valeria Burkovskaya, Preena Patel, Ashley Young, Melanie Racenstein, Tinamarie Bauman, Wassim Mchayleh, Deborah Toppmeyer, Shridar Ganesan, Barry Rosen, Angel Rodriguez, Minetta Liu. Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer [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 PO4-15-12.

Abstract PO5-01-02: A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III

Abstract Background In 2018 the TRAIN-2 clinical trial demonstrated that in stage II–III HER2-positive breast cancer, the use of a neoadjuvant non-anthracycline chemotherapy regimen of 9 cycles of TCHP [paclitaxel and carboplatin (AUC 6 mg/mL/min) with trastuzumab and pertuzumab resulted in lower toxicity and comparable pathological complete responses to an anthracycline based regimen. A pathological complete response was recorded in 141 (67%) of 212 patients in the anthracycline group and in 140 (68%) of 206 in the non-anthracycline group. Our primary aim was to identify rates of pathological complete response and rates of toxicity with a less intensive regimen of 6 cycles of TCHP where carboplatin was dose adjusted to AUC5. Methods In this single center cohort study, we reviewed patients with stage II-III Her2-positive breast cancer who received a modified chemotherapy regimen of 6 cycles of neoadjuvant paclitaxel (80 mg/m2 days 1 and 8) and reduced dose of carboplatin (AUC= 5 mg/mL/min) with trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks from 2021- June 2023. Clinicopathologic data, the number and length of treatment delays, treatment related toxicities of all grades, and pCR rate were extracted from the electronic medical record. Results 32 patients were included in the analysis. The median age of the cohort was 51 years (30-65). No patient had a BRCA mutation. 20 (62.5%) had T1-2 disease and 12 (37.5%) had T3-4 disease. 14(43.75%) patients had N0 disease and 20 (62.5%) had N1-3 disease. ECOG Performance status was 0, 1 and 2 in 26 patients (81.25%), 4 (12.5%) patients and 2(6.25%) patients respectively. At the time of analysis, 2 patients (6.25%) were continuing active treatment, while 30 (93.75%) had completed planned neoadjuvant therapy and underwent surgery. Of patients who completed planned neoadjuvant therapy, 6 patients (18.75%) had 1 or more hospitalisations due to toxicity. 10 patients (31.25%) required dose reductions and 3(9.38%) had early treatment discontinuation. Rates of adverse events will be presented. pCR rate was 60 % (N=18/30). 19 (63%) of 30 patients underwent mastectomy and 11 (36.7%) underwent breast-conserving surgery. Updated analysis will be included at time of presentation. Conclusion In this single-center retrospective study of patients receiving a modified version of TCHP we found a 60% pCR rate. The rate of dose reductions and treatment discontinuations appears favorable with use of this modified regimen. This was in a heterogeneous population of patients treated in routine clinical practice where there was a high rate of patients with locally advanced disease. Limitations of our study include immaturity of data and small sample size; however, these data warrant further exploration through longer-term follow-up and multi-center validation. Citation Format: Carolyn Moloney, Maggie Louise O'Connor, Caroline O'Leary, Aislinn Reilly, Simon Barry, David O'Reilly, Philip Bredin, Hadia Paryani, David Solaligue, Bryan Hennessy, Megan Greally, Patrick G. Morris. A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III [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 PO5-01-02.

Abstract PS14-06: Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522

Abstract Title: Real-world analysis of adverse events in patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. To date, real world outcome analyses are limited. Methods: In this retrospective, multicenter study, we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 as SOC. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: 577 pts were included in this analysis. The median age of the cohort was 52 [range 27-77]. 457 pts had T1-2 disease and 139 had T3-4 disease. 316 pts had N0 disease and 261 had N1-3 disease. 506 pts had baseline ECOG 0, 62 had ECOG 1, and 9 had ECOG 2-3. Of the 482 patients who had surgery at the time of this analysis, 219 patients had pCR (54.5%) and 192 pts were still receiving treatment. 217 patients (37%) had an adverse drug event (ADE) causing dose reductions and 228 patients (39.5%) had to discontinue treatment early. There were 360 unplanned care visits, with 91 patients having 2+ visits. 66 patients had hospitalizations due to the regimen with 102 total hospitalizations. 179 (31%) of patients had grade 3+ immune related adverse events (irAEs), including many that are rare and potentially serious. 317 (54%) had an immune related adverse effect (see Table 1). There was no significant difference in the frequency of grade 3+ irAE based on age or body mass index. We observed no difference in residual disease between patients who discontinued treatment early and those who did not. However, if patients had an ADR causing a dose reduction, pts were significantly more likely to have residual disease (P=0.039) Conclusions: In a multicenter real-world analysis, the KEYNOTE-522 regimen was associated with a high frequency of dose reductions, early treatment discontinuations, ER visits, and hospitalizations. This may have accounted for a lower pCR rate than observed in the landmark clinical trial. Most grade 3+ irAEs occurred at greater frequency in our real-world analysis. Providers should carefully monitor for toxicity to ensure optimal patient outcomes. Table 1 Citation Format: Mara Hofherr, Katherine Clifton, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Traci White, William Adler, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Andrew Davis. Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522 [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 PS14-06.

Abstract PO4-17-03: Neoadjuvant chemotherapy in invasive lobular carcinoma of the breast: A retrospective study on survival outcomes

Abstract Background: Neoadjuvant chemotherapy (NAC) is a well-established component of breast cancer management. Invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) are often treated similarly, but many studies are demonstrating a major difference in treatment responses according to the histopathological type of cancer. Aim: To evaluate the overall survival of patients with ILC after NAC compared with adjuvant chemotherapy. Methods: This retrospective cohort study included patients treated for breast ILC between 1998 and 2016 at the Center for Breast Diseases of de CHU de Québec – Université Laval, a tertiary breast cancer center. The primary outcomes were the overall survival (OS) and the recurrence-free survival (RFS) of ILC patients receiving NAC compared with patients who received only adjuvant chemotherapy. The follow-up was censored at the last hospital contact. The secondary outcomes were the locoregional recurrence, pathological complete response (pCR), and pCR impact on survival. Results: During the study period, 265 women were treated for ILC, of which 72 had NAC, and 193 had adjuvant therapy. No significant differences were observed regarding the patient’s characteristics (age, BMI, smoking, menopausal status, and use of hormonal replacement therapy). A T4 disease was found in 29.2% of the NAC group (vs. 0 in the adjuvant group), but the N2-3 rate was lower in the NAC group (5.6% vs. 22.3%, P=0.011). More patients in the NAC group underwent mastectomy (65.3% vs. 29.5%, P< 0.0001) and axillary dissection (80.6% vs. 50.8%, P< 0.0001). Three (4.2%) patients in the NAC group achieved a pCR. The rates of radiotherapy (P=0.851) and hormonal therapy (P=0.694) were similar between the two groups. The mean follow-up was 8 years. After adjustment for age, T, N, surgery type, radiotherapy, and hormonal therapy, the NAC group showed significantly lower 10-year OS (56.2% vs. 80.7%, P< 0.0001) and RFS (51.8% vs. 72.7%, P=0.0004) compared with the adjuvant group. There were no differences in the 10-year local recurrence rate (90.6% vs. 93.5%, P=0.11). In a Cox regression analysis of RFS considering the previously mentioned covariables, more events in the NAC group (OR=2.52, 95%CI: 1.39-4.58, P=0.002) and patients with N2-N3 (OR=3.68, 95%IC: 2.00-6.80, P< 0.01). Conclusion: Despite the general belief that ILC and IDC should be treated similarly, this study strongly suggests that ILC seems to have a poorer response to NAC. Patients diagnosed with ILC might benefit from a more aggressive surgical approach followed by adjuvant chemotherapy, no matter the severity of the disease. Additional long-term prospective comparative studies are needed to support this statement and improve the management of these patients. Citation Format: Virginie Gauthier, Anne-Julie Simard, Christine Desbiens, Brigitte Poirier, Julie Lemieux, Dominique Boudreau, Dominique Leblanc, Claudya Morin, Jean-Charles Hogue, Éric Poirier. Neoadjuvant chemotherapy in invasive lobular carcinoma of the breast: A retrospective study on survival 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 PO4-17-03.

Abstract PO5-03-11: Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study

Abstract Background In India, the majority of patients with triple negative breast cancer(TNBC) present with locally advanced and often inoperable disease due to lack of screening, awareness, and social stigma. This makes pathological complete response(pCR) after neoadjuvant chemotherapy(NAC) less likely, leading to early recurrence and poor survival outcomes. Immune checkpoint inhibitors(ICI) in addition to platinum agents have improved both pCR and disease-free survival(DFS). However, these are accessible only to a very small proportion(< 3%) of patients in LMICs due to exorbitant costs. The activity and cost-effectiveness of low dose ICI has been demonstrated in head and neck. The efficacy of low dose ICI in the neoadjuvant setting for TNBC has not been studied. We examined our outcomes with ultra-low dose nivolumab(< 0.6 mg/kg every 2 weeks) added to NAC for locally advanced and borderline operable TNBC. Methods A retrospective analysis of 132 patients with TNBC who received NAC with the ddDCEP regimen(Docetaxel 75mg/m2 and Cyclophosphamide 600 mg/m2 alternating with Epirubicin 90mg/m2 and Cisplatin 60mg/m2 every 2 weeks for 8 cycles) or ddDCEP plus low dose nivolumab(< 0.6mg/kg/2 weeks) and underwent mastectomy at our centre between 2018-2023 was carried out. 105 and 27 patients received ddDCEP alone and ddDCEP + low dose nivolumab respectively. Using rigorous exact matching, 26 matched pairs(52 patients) were obtained based on tumour grade and AJCC TNM stage. pCR in the surgical specimen was the principal outcome assessed. Survival data, adverse events and cost were also analysed. Results The median age of cases and controls was 42 and 40 years respectively. Tumour histology was ductal carcinoma most patients. Across both groups the stage distribution was the same with nearly 85% stage III(IA 3.8%;IIB 7.7%; IIIA 23.1%;IIIB 43.2%;IIIC 19.2%). 92% of cases and 85% of controls had node positive disease. 62% of cases and 46% of controls had T4 disease. At a median follow up of 9 months, there were no recurrences or deaths among the cases. The most common immune mediated adverse event was hypothyroidism seen in 11.5% of cases. The rates of grade 3/4 anaemia, thrombocytopenia and febrile neutropenia were approximately 38%, 10% and 3.8% across cases and controls respectively. The median dose of nivolumab was 0.27mg/kg/2weeks as opposed to the approved dose of 3mg/kg/2weeks for most indications. The range of doses varied from 0.07 to 0.58mg/kg/2weeks. In the overall cohort, the addition of nivolumab did not have any apparent effect on the pCR rates which were identical at 42.3% in both cases and controls. However, there was a positive correlation between the total dose of nivolumab/kg(body weight) and the likelihood of pCR(coefficient 0.34; p-value 0.046). Patients who received higher than the median dose of nivolumab had a significantly higher likelihood of attaining pCR than those who received lower doses (69.2% pCR vs.15.4%;p-value 0.015). The cost of nivolumab at 0.6 mg/kg for 4 doses is approximately USD2000 compared to USD34400 for 8 doses of pembrolizumab in the neoadjuvant component of the KEYNOTE-522 regimen. Conclusion In this cohort with locally advanced/inoperable TNBC, the addition of ultra-low dose nivolumab did not improve pCR overall compared to a matched control set who did not receive ICI. However, in the subset of patients who received between 0.27-0.58 mg/kg/2weeks, the pCR rates were significantly higher at 69%. This presents a promising and cost-effective approach for TNBC management in LMICs. This effect needs verification in larger phase II/III trials. Table. Citation Format: Zachariah Thomas, Josh Georgy, Ashish Singh, Anjana Joel, Divya Thumaty, Ajoy John, Jerryes Wisely, Grace Rebekah, Elanthenral Sigamani, Anish Cherian, Deepak Abraham, Paul Jacob, Rajesh Balakrishnan, Patricia Solomon, Selvamani Backianathan, Raju Chacko. Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study [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 PO5-03-11.

Abstract PO2-02-05: CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial

Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor >10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 < 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [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 PO2-02-05.

Clinical Outcomes in T4 and/or N2 Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy: A Retrospective Study

IntroductionTotal neoadjuvant therapy (TNT) in the management of locally advanced rectal cancer (LARC) did not show survival benefit over the standard long course chemoradiotherapy. Trials of TNT did not address the impact of each risk feature in isolation from other high-risk features. MethodologyIn this retrospective study, we describe the clinical outcomes of patients with T4 and/or N2 rectal adenocarcinoma who were treated with chemoradiotherapy followed by total mesorectal excision (TME). After obtaining the local regulatory approvals, demographic and clinical data were collected for patients in Manitoba between January 2007 and December 2019. ResultsThe cohort included 331 patients. 61 patients had T4-only disease and 218 had N2-only disease. Mean age was 59.65 years. 74.3% received adjuvant chemotherapy (ACT), but only 56.5% completed the planned course. R0 resection was achieved in 93.4% of patients (78.7% and 97.2% in T4 and N2, respectively). Median follow up was 4.93 years. 3-year overall recurrence rate was 29%. 3-year locoregional recurrence (LRR) rate was 8% (16% and 6% in T4 and N2, respectively). 3-year overall survival (OS) rate was 84% in the whole cohort (72.6% and 87.1% in T4 and N2, respectively). Incomplete surgical resection was a poor prognostic factor for both OS and LRR. ACT was associated with a survival benefit in the whole cohort (P = .001) and in the N2 sub-cohort (P = 003) but there was no survival benefit observed in T4 sub-cohort. ACT did not have an impact on LRR. ConclusionsAchieving R0 resection in LARC with neoadjuvant therapy improves recurrence and survival rates. T4 disease carries a worse clinical outcome than N2 and consideration should be given to upstage T4 to stage III. Different high-risk features in LARC predict different clinical outcomes. In the era of TNT, personalization of treatment strategy based on these factors could potentially improve outcomes.

Does the use of intraoperative frozen section of bone marrow from the cut end of the mandible help assess the adequacy of bone margins following mandibulectomy for oral cancer?

The adequacy of the cut end of the mandible following a segmental mandibulectomy done for oral cancer intraoperatively is at times assessed using a frozen section (FS)of the bone marrow (BM)at the cut ends. The study aimed to assess its utility to guide the intraoperative decision on the adequacy of bony margins. All patients with oral squamous cell carcinoma (OSCC)who underwent segmental mandibulectomy from January 2012 to December 2021 at our institute and for whom intraoperative FS of BM was utilized were included. We analyzed the sensitivity, specificity, and positive and negative predictive value (PPV,NPV) of this in predicting positive bone margins. A total of 457 patients were included in the study. The majority of the cases were per premium cases (n = 372, 81.4%). The median age of the cohort was 52 years (range: 22-80 years). Most patients had T4 disease (n = 406, 88.8%). On FS, BM was positive in only 18 patients (3.9%) for whom the bone margin was revised. BM biopsy report in the final histopathology was positive in 12 patients (2.2%). The sensitivity, specificity PPV, and NPV were 52.3%, 98.65%, 64.7%, and 97.7% respectively. No factors predicting BM positivity on FS could be identified in this cohort. The BM FS was positive in only a small percentage of patients, and it helped in reducing the bone margin positivity rate from 3.9% to 2.2% only. Hence the intraoperative BM FS seems to have limited utility as seen from our study.

A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

TRNA-Derived Fragments as Biomarkers in Bladder Cancer.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small noncoding RNA such as transfer RNA-derived fragments (tRF) and microRNA. Here, we performed small-RNA next-generation sequencing from EVs from urine and serum, as well as from serum supernatant. RNA was extracted from 15 non-cancer patients (NCPs) with benign findings in cystoscopy and 41 patients with non-muscle invasive BC. Urine and serum were collected before transurethral resection of bladder tumors (TUR-b) and at routine post-surgery check-ups. We compared levels of tRFs in pre-surgery samples to samples from NCPs and post-surgery check-ups. To further verify our findings, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between T1 stage BC patients and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing pre-surgery to post-surgery samples and four DEtRFs were found when comparing pre-surgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

Long-term survival in patients with brain-only metastatic non-small cell lung cancer undergoing upfront intracranial stereotactic radiosurgery and definitive treatment to the thoracic primary site

Background and purposeTo evaluate modern clinical outcomes for patients with brain-only metastatic non-small cell lung cancer (NSCLC) treated with intracranial stereotactic radiosurgery (SRS) with or without definitive treatment of the primary site. Materials and methodsPatients with synchronously diagnosed NSCLC and brain-only metastatic disease treated with intracranial SRS at a single institution were retrospectively identified. Patients were stratified based on whether they did (A) or did not (B) receive definitive primary site treatment. Patient characteristics and clinical outcomes were compared. ResultsFrom 2008 to 2022, 103 patients were identified, 53 of whom received definitive primary site treatment. Median follow-up was 2.1 y (A) and 0.8 y (B) (p < 0.001). 28 (53 %) patients in Group A received immune checkpoint inhibitor (ICI) therapy versus 19 (38 %) in Group B (p = 0.13) and there were no other statistically significant baseline or treatment characteristic differences between the groups. 5-year local-PFS was 34.5 % (A) versus 0 % (B) (p < 0.001). 5-year regional-PFS was 33.0 % (A) versus 0 % (B) (p < 0.001). 5-year distant body-PFS was 34.0 % (A) versus 0 % (B) (p < 0.001). 5-year CNS-PFS was 14.7 % (A) versus 0 % (B) (p = 0.12). 5-year OS was 40.2 % (A) versus 0 % (B) (p = 0.001). 5-year CSS was 67.6 % (A) versus 0 % (B) (p = 0.002). On multivariable analysis, lack of definitive treatment to the primary site (HR = 2.40), AJCC T3-4 disease (HR = 2.73), and lack of ICI therapy (HR = 2.86) were significant predictors of death. ConclusionDefinitive treatment to the thoracic primary site in patients with brain-only metastatic NSCLC after intracranial radiosurgery was associated with slower progression of disease and improved survival.

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

Abstract 2400: Determinants of early recurrence in surgically-resected colon cancer: A multi-omics analysis

Abstract Introduction: Colon cancer is the third most common cancer worldwide. The mainstay treatment for localized disease is surgical resection, often followed by adjuvant chemotherapy in stage III patients, and stage II patients with high-risk features. Unfortunately, some patients experience early local and/or distant recurrence. Besides classic anatomical/pathological tumor features, insight into the genomic determinants of early recurrence in colon cancer is lacking. Herein, we utilize a multi-omics approach to identify early-recurrence-specific features that could aid in more accurate risk stratification. Methods: We utilized the Cancer Genomic Atlas Colon Adenocarcinoma (TCGA-COAD) Database. Clinical, histopathological and genomic data were retrieved through the cBioPortal database. Our analysis was limited to patients with stage 2 or 3 (n = 390) disease based on the American Joint Committee on Cancer Code. Early recurrence (ER) was defined as disease relapse/recurrence within 12 months of sample acquisition post-surgery. Accordingly, patients were categorized into the ER and non-early recurrence (NER) groups based on a cut-off point of 12 months of disease-free survival. Results: The colon cancer ER and NER group included 45 and 345 patients, respectively. Comparable age, sex and race percentages were found between both groups. The ER group had significantly worse overall, progression-free, and disease-specific survival (HR: 0.083 95% CI: 0.031-0.220, HR: 0.035 95% CI: 0.011-0.0109, HR: 0.021 95% CI: 0.006-0.076, respectively). ER patients had a significantly higher proportion of patients with T4 and N2 disease based on the TNM staging system. ER patients had significant (P&amp;lt; 0.05) expression of TRIM46, TRPC4, ELOVL7, CSMD1, BCLAF1, and CD70 mutations, while tumor mutational burden was comparable between both groups (median TMB in ER vs NER: 4.2 vs 3.62, p = 0.28). Differential gene expression analysis revealed 68 genes to be upregulated in the ER group which were found to be enriched in hypoxia and interleukin-11 pathway genes. Genes upregulated in the NER group (n = 49) were enriched in interferon-alpha response and glycolysis/gluconeogenesis pathway genes. Proteomics analysis revealed significantly higher levels of EIF4E, CCNE1, SRSF1, SCD, and PECAM1 proteins in NER patients .Conclusion: Our results highlight insights into molecular and genomic features unique to colon cancer patients with early recurrence. Understanding such predictors for early recurrence will aid in risk stratification and help in determining patients who would derive the most benefit from adjuvant treatment considerations. Citation Format: Salma Al-Aomar, Hassan Abushukair, Alaa Zaitoun, Sara Zytoon, Sara Illeyyan, Husam Almomani, Ghayda'a Al-Majali, Arafat Hammad, Khaled Obeidat, Fuad Turfah, Awni Shahait, Fadwa Ali. Determinants of early recurrence in surgically-resected colon cancer: A multi-omics analysis [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 2400.

Clinical Outcomes in Adenoid Cystic Carcinoma of the Nasal Cavity and Paranasal Sinus: A Comparative Analysis of Treatment Modalities.

This study aimed to present the treatment patterns and outcomes for adenoid cystic carcinoma (ACC) arising in the nasal cavity and paranasal sinus. Sixty-one sinonasal ACC patients were retrospectively reviewed: 31 (50.8%) underwent surgery followed by postoperative radiation therapy (S+PORT), and 30 (49.2%) received definitive radiation therapy (D(C)RT). T4 disease was significantly more frequent in the D(C)RT group (25.8% vs. 80.0%, p < 0.001), where all T4b disease patients underwent D(C)RT. The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival were 61.8% versus 37.8% (p = 0.003), 64.8% versus 38.1% (p = 0.036), 52.6% versus 19.3% (p = 0.010), and 93.2% versus 73.4% (p = 0.001) in the S+PORT and D(C)RT groups, respectively. The absolute differences in 5-year rates of LFFS, DMFS, and PFS between the two groups were smaller in the T3-4 subgroup. The univariate analysis showed that T4b disease, neurologic symptoms, longest diameter of tumor, radiological evidence of nerve involvement, and undergoing D(C)RT were associated with worse clinical outcomes, but the significance disappeared in the multivariate analysis, except for in the case of radiological evidence of nerve involvement. In conclusion, most patients with extensive disease underwent upfront D(C)RT and generally exhibited inferior clinical outcomes when compared to those with less extensive disease and who underwent S+PORT.

Pilot Study: Prophylatic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Cancers at High Risk of Developing Peritoneal Metastases in a Tertiary Asian Centre

Introduction: The second most common site of Colorectal Cancer (CRC) recurrence is the peritoneum. The primary aim of this study was to assess feasibility of prophylactic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Asian patients, and to determine the associated morbidity and time to start of adjuvant chemotherapy. Materials and methods: Patients at high-risk of developing Peritoneal Metastases (PM) include the following: T4 on imaging, krukenburg tumours, perforated tumours, limited synchronous PM, and peritoneal fluid cytology positive for malignant cells. Recruited patients were divided into two groups; newly diagnosed CRC patients with any of the high-risk features (Group 1), and patients who had recent surgery (less than 8 weeks from recruitment) with histological confirmation of high-risk features (Group 2). Results: 12 patients were recruited, of which there were 10 Group 1 patients and 2 Group 2 patients. Of the 10 patients in Group 1, 7 had T4 disease and another 3 had limited PM suspected on staging scans. All patients completed the Cytoreductive Surgery (CRS) and HIPEC procedure with no mortalities. 2 patients experienced major morbidity. Median time to adjuvant chemotherapy was 46 days (IQR 42.75-52.85). Median Length of Stay (LOS) was 13.5 days (IQR 8-15) comparable to our control group (N=214), which included all patients undergoing CRS and HIPEC with a median LOS of 14 days (IQR 11-19, p=0.11). Conclusion: Prophylactic HIPEC is feasible in a highly selected group of patients with newly diagnosed locally advanced CRC and those with limited synchronous PM, with appropriate time to receiving adjuvant chemotherapy.

21 Gy single fraction prostate HDR brachytherapy: 5-year results of a single institution prospective pilot study

PURPOSETo present the outcome and toxicity results of a prospective trial of 21 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- or intermediate-risk prostate cancer. METHODS AND MATERIALSPatients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had low- or intermediate-risk prostate cancer with tumor stage ≤ T2b, PSA ≤ 15, and Gleason score ≤ 7. Patients underwent trans-rectal ultrasound-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy to a dose of 21 Gy. The primary endpoint was grade ≥ 2 urinary/GI toxicity rates. RESULTSTwenty-six patients were enrolled with a median follow up of 5.1 years and median age of 64 years. 88.5% of patients had T1 disease, 15.4% had Gleason score 6 (84.6% Gleason 7), and median pre-treatment PSA was 5.0 ng/mL. Acute and chronic grade ≥ 2 urinary toxicity rates were 38.5% and 38.5%, respectively. There were no grade ≥ 2 acute or chronic GI toxicities. Six (23.1%) patients experienced biochemical failure, six (23.1%) patients experienced radiographic local failure, and five (19.2%) patients had biopsy-proven local failure. No patients developed regional lymph node recurrence or distant metastasis. 5-year overall survival and cause-specific survival were 96.2% and 100%, respectively. CONCLUSIONS21 Gy single fraction HDR brachytherapy was associated with modestly higher-than-anticipated chronic urinary toxicity, as well as high biochemical and local failure rates. The results from this prospective pilot study do not support the use of this regimen in standard clinical practice.

Unveiling the challenges of UTUC biopsies and cytology: insights from a global real-world practice study

PurposeDiagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology.MethodsTo evaluate endoscopic biopsy techniques and outcomes, we assessed data from patients from the CROES-UTUC registry. The registry includes multicenter prospective collected data on diagnosis and management of patients suspected having UTUC.ResultsWe assessed 2380 patients from 101 centers. dURS with biopsy was performed in 31.6% of patients. The quality of samples was sufficient for diagnosis in 83.5% of cases. There was no significant association between biopsy techniques and quality (p = 0.458). High-grade biopsy accurately predicted high-grade disease in 95.7% and high-risk stage disease in 86%. In ureteroscopic low-grade tumours, the prediction of subsequent low-grade disease was 66.9% and low-risk stage Ta-disease 35.8%. Ureteroscopic staging correctly predicted non-invasive Ta-disease and ≥ T1 disease in 48.9% and 47.9% of patients, respectively. Cytology outcomes did not provide additional value in predicting tumour grade.ConclusionBiopsy results adequately predict high-grade and high-risk disease, but approximately one-third of patients are under-staged. Two-thirds of patients with low-grade URS-biopsy have high-risk stage disease, highlighting the need for improved diagnostics to better assess patient risk and guide treatment decisions.Clinical trial registration: The study was registered at ClinicalTrials.gov (ClinicalTrials.gov NCT02281188; https://clinicaltrials.gov/ct2/show/NCT02281188).

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.