Baseline Tumor Characteristics Research Articles

Tumor-agnostic genomic and clinical analysis of solid tumors with BRAF fusions.

3146 Background: Approximately 15% of cancers harbor BRAF alterations, of which ~5% are BRAF fusions. BRAF fusions are class II alterations that have worse outcomes than class I V600E alterations. While prior investigational therapies for BRAF fusions had disappointing outcomes, novel therapies are in clinical trials, underscoring the need to better characterize these tumors. Methods: Data from adult and pediatric patients with BRAF fusion+ cancers identified between January 2014 and November 2022 utilizing a center-wide next generation sequencing (NGS) program of >99,000 sequenced samples were analyzed. DNA-based hybrid capture tumor NGS (MSK-IMPACT), ctDNA targeted NGS (MSK-ACCESS), and/or RNA anchored multiplex PCR tumor NGS (MSK-Fusion) were used. Fusions were manually reviewed and considered to have oncogenic potential if they had an in-frame protein fusion involving a non-BRAF partner gene and an intact BRAF kinase domain (exons 11-18). Fusions not previously reported in OncoKB, COSMIC, TCGA, NIH gene, Fusion GDB2, and PubMED were classified as novel. All cases underwent clinical data curation including baseline demographic, tumor characteristics, and treatment histories. Results: 212 patients (0.2%) with BRAF-fusion positive solid tumors were identified. 194 were identified by DNA-based tumor NGS (96 had sufficient tissue for confirmatory RNA-based NGS, all of which were positive). Six were identified by ctDNA NGS and 12 by RNA-based tumor NGS only (5 had insufficient tissue for DNA-based tumor NGS). 83 unique 5’ fusion partners were found, of which 42 were novel. The most frequent tumor types were pilocytic astrocytoma (n=30, 14%), prostate CA (n=28, 13%), melanoma (n=24, 11%), lung CA (n=21, 10%), and colon CA (n=15, 7%). 44% of patients with pilocytic astrocytoma had BRAF fusions, of which 90% were BRAF-KIAA1549. Concomitant alterations (≥10% frequency) included TP53 (24%), TERT (18%), CDKN2A deletions (13%), and CDKN2B deletions (12%). 20% (n=43) were treated with MAPK-pathway directed therapies spanning multiple histologies and lines of therapies. Of the 212 patients, 17 had acquired BRAF fusions after targeted therapy for another oncogene ( EGFR mutation (n=11), BRAF V600E (n=4), FGFR fusion (n=1), NTRK fusion (n=1)). The majority of patients with acquired BRAF fusions had EGFR-mutant lung adenocarcinoma (n=11, 76%); the median time from EGFR targeted therapy initiation to BRAF fusion detection was 25 months (range 16-38 months). Conclusions: A wide variety of adult and pediatric solid tumors harbored de novo BRAF fusions. Complementary RNA sequencing optimized fusion identification in many cases. Multiple novel fusion partners were found. Acquired BRAF fusions were identified after targeted therapy for a variety of distinct oncogenes, the majority of which were EGFR mutations.

Predictors of Nodal Disease in Rectal Cancer Patients with Complete Mucosal Response to Neoadjuvant Therapy.

Some patients with locally advanced rectal cancer (LARC) achieve complete mucosal response following neoadjuvant therapy (NAT) and may be candidates for watch and wait strategy. This study aimed to identify predictors of nodal disease in patients with LARC who had a complete mucosal response to NAT. This case-control study included patients with LARC who were treated with NAT in the National Cancer Database between 2004 and 2019. Patients with complete mucosal response, defined as pathologic T0, were identified and classified according to the status of the pathologic N stage into complete response (pT0, pN0) and complete mucosal response with positive nodal disease (pT0, pN +). The two groups were compared regarding baseline demographics and tumor characteristics to determine the predictors of nodal disease after NAT. A total of 5529 patients (59.7% male) with a mean age of 59.6 ± 12.2years had a complete mucosal response following NAT. Nodal disease was detected in 443 (8%) patients with a complete mucosal response. Independent predictors of nodal disease were clinical N + stage (OR: 1.87, p < 0.001), mucinous histology (OR: 3.8, p = 0.003), and lymphovascular invasion (OR = 4.01, p < 0.001). The clinical T stage was inversely related to the risk of nodal disease. Despite having a complete mucosal response following NAT, 8% of patients had nodal disease. Clinical evidence of nodal involvement on preoperative assessment, mucinous tumor histology, and lymphovascular invasion predicted nodal disease after NAT. These findings should be considered when making a decision on watch and wait strategy in patients with clinical complete response.

Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.

To evaluate the differences in nodal positivity if the sentinel lymph node biopsy (SLNB) is performed before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and its impact on prognosis. A retrospective cohort study was performed in a single center including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2-negative (HR + /HER2-) breast cancer, treated with NET and SLNB. SLNB was done pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB macrometastasis, although in selected elderly patients, it was omitted. Kaplan-Meier survival curves were estimated in relation to the status of the axilla, and the differences assessed using the log-rank test. Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. Both groups were similar in baseline tumor and patient characteristics. SLNB positivity was similar regardless of whether SLNB was performed before (5/14, 35.7%) or after NET (27/77, 37%), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following ALND. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8%, respectively, with no significant differences according to SLNB status (p 0.5 and 0.8, respectively). SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients.

Abstract 1394: Comprehensive clinical and genomic analysis for patients with MYC, MYCN, and MYCL amplified solid tumors

Abstract Introduction: The MYC gene family (MYCf), which includes MYC, MYCN, and MYCL, is deregulated in ~70% of cancers and is associated with treatment resistance. Whereas older investigational therapies for MYC amplified tumors were unsuccessful, promising novel targeted therapies are in early phase clinical trials. Unfortunately, it remains unclear how to select patients whose cancers may harbor true MYC addiction. We thus sought to characterize factors such as amplification level, focality, and clonality that may correlate with increased MYC dependence. Methods: Utilizing a center-wide next generation sequencing (NGS) program of &amp;gt;71,000 sequenced patients, genomic and clinical data from pediatric and adult patients with MYC, MYCN, and MYCL amplifications were identified between 2014 and 2022. Patients were characterized as harboring MYC, MYCN, and MYCL amplification based on a read-depth methodology using a DNA-based hybrid-capture NGS (MSK-IMPACT) and Fraction and Allele-Specific Copy Number Estimates from the Tumor Sequencing (FACETS). All cases underwent clinical data curation including baseline demographic, tumor characteristics, and treatment histories. Results: We identified 3911 cancers with MYCf amplification (n=3257 (82%) MYC; n=364 (9%) MYCL; n=330 (8%) MYCN) across 40 malignancies, for an overall 5.5% incidence. The most frequent tumor types with MYCf amplification were breast (22%), non-small cell lung (NSCLC) (11%), colorectal (8%), ovarian (8%), prostate (7%), brain (5%), and small cell lung cancers (SCLC) (2%). Cancers with MYC amplification had longer segment lengths than MYCL and MYCN amplification, which appeared more focal (median = 19, 4.3 and 4.5 MB, respectively, p &amp;lt; 0.001). MYCN amplified cancers had higher total copy number than MYC and MYCL amplified cancers (median = 19, 8, 9, respectively, p &amp;lt; 0.001). MYC, MYCN, and MYCL samples were predominantly clonal (median clonal fraction &amp;gt; 99% for all genes). Most NSCLC, squamous cell lung cancers, and pulmonary carcinoids had MYC amplifications (93%, 70%, and 67% respectively). Conversely, SCLCs most often had MYCL amplifications (49%). No concurrent targetable driver alterations were found in 33% of metastatic NSCLCs with MYC, 75% of MYCN, and 6% of MYCL amplifications. Conclusions: While MYCf amplification is observed across a broad range of cancer types, factors such as gene type (MYC, MYCN, MYCL), focality, total copy number, clonality, and concurrent oncogenic drivers vary widely. Novel MYC-directed trials may consider enrichment for a subpopulation of cancers with higher-level, focal, and clonal MYCf amplifications without concurrent other drivers. Citation Format: Monica F. Chen, Allison Richards, Patrick Evans, Patrick Lee, Adam Price, Matteo Repetto, Soo Ryum Yang, Jason Chang, Rose Brannon, Ezra Rosen, David Brown, Charles Rudin, Nitya Raj, Mark G. Kris, Jorge Reis-Filho, Mark Donoghue, Alexander E. Drilon, Noura J. Choudhury. Comprehensive clinical and genomic analysis for patients with MYC, MYCN, and MYCL amplified solid tumors [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 1394.

Serum Inflammation Parameters and Survival in Hepatocellular Carcinoma Patients: Importance of Albumin and Gamma-Glutamyltranspeptidase

Introduction: Many single and combination blood tests that reflect local or systemic inflammation have been shown to be useful prognosticators in patients with a variety of tumor types. To try to clarify, this issue in patients with nonsurgically treatable hepatocellular carcinoma, multiple serum parameters were evaluated for their relationship to survival. Methods: A prospectively collected database was interrogated of 487 patients with known hepatocellular carcinoma and documented survival and having all the inflammation parameters of interest in this study, together with baseline tumor characteristics from CT scans. Serum parameters included NLR, PLR, CRP, ESR, albumin, and GGT. Results: All the parameters had significant hazard ratios on Cox regression model. Combination double parameters with hazard ratios >2.0 were: ESR plus GGT, albumin plus GGT, albumin plus ESR. The triplet combination of albumin plus GGT plus ESR had a hazard ratio of 6.33. Using Harrell’s concordance index (C-index), the highest inflammation-based 2-parameter prognostic score was for albumin plus GGT. When clinical characteristics of patients with high values for albumin plus low values for GGT were compared to low values for albumin plus high values for GGT (worse prognosis), statistically significant differences were found for tumor size, tumor focality, macroscopic portal vein invasion, and serum alpha-fetoprotein levels. Addition of ESR did not provide additional tumor information. Conclusion: The combination of serum albumin plus GGT levels was the most prognostically useful among the inflammation parameters that were tested, and reflected significant differences in tumor aggressiveness characteristics.

Abstract P5-08-17: Monitoring for cardiotoxicity in early breast cancer: an Australian experience

Abstract Background Breast cancer is the most commonly diagnosed cancer in Australia. Patient outcomes continue to improve with current 10 year survival of 86%. Given this, greater focus is needed to minimise potential long term toxicities of prescribed therapies. Anthracyclines and HER2 targeted therapies are commonly prescribed agents for high risk early breast cancers and are associated with acute and long term cardiotoxicity. Despite this, screening of cardiotoxicity in Australian patients receiving these therapies remains variable due to a lack of endorsed national screening guidelines. We conducted a retrospective review of screening procedures for cardiotoxicity in 2 major oncology centres in metropolitan Sydney and compared the findings to current international recommendations from ASCO/ESMO guidelines. Methods Patients were included if they received doxorubicin, epirubicin or trastuzumab with neoadjuvant or adjuvant intent during 2021. Baseline patient and tumour characteristics including cardiovascular risk factors were reviewed. Baseline ECG, transthoracic echocardiogram (TTE) or cardiac biomarkers (cardiac troponin or brain natriuretic peptide) were recorded, as well as frequency of serial monitoring and incidence of cardiotoxicity and cardiology referrals. Results 111 patients receiving initial curative therapy were included of which 45 received anthracycline therapy without trastuzumab. 66 received trastuzumab of which 34 also received anthracycline. 38 patients were aged greater than 60 and 31 had 2 or more cardiovascular risk factors. Of the patients receiving anthracycline only, 96% had a baseline TTE. All patients receiving trastuzumab only had a baseline TTE and of the 34 patients who received anthracycline and trastuzumab 3 did not undergo baseline TTE but underwent one prior to commencing trastuzumab. 3 patients total had a baseline ECG. No patients had baseline biomarkers measured. Only 5 patients had biomarkers measured at 1 year and all 5 had developed grade 1 heart failure on treatment. These 5 patients were referred for cardiology review and 2 required an interruption of trastuzumab. All patients receiving trastuzumab underwent 3 monthly TTEs on treatment. Of the 35 patients now more than 1 year post treatment completion, only 3 patients had a TTE at 12 months. No patients referred to cardiology have reached 12 months post treatment. Discussion International guidelines recommend screening to identify and treat early cardiotoxicity and prevent long term morbidity. ASCO and ESMO guidelines both recommend patients receiving anthracycline undertake a TTE at baseline and at 6-12 months after completing therapy. Both recommend 3 monthly TTEs for patients receiving trastuzumab. The ESMO guidelines recommend a baseline ECG and consideration of further TTE at 2 years post therapy. For high risk patients the ASCO guidelines discuss offering routine TTEs during treatment. The ESMO guidelines recommend measurement of cardiac biomarkers for patients receiving anthracycline prior to each cycle and routine monitoring can be considered for patients receiving anti HER2 therapy. The ASCO guidelines reserve use of cardiac biomarkers for patients who develop signs or symptoms of cardiac dysfunction. Our study demonstrates that while baseline cardiac assessment is well performed a personalised approach to cardiac monitoring during curative therapy is not. These were unexpected findings given both treatment units are located in well resourced areas of Sydney. An outcome of this study has been the development of a cardio-oncology group within our oncology and cardiology departments. This has led to the development of new clinical guidelines to screen and manage high risk breast cancer patients receiving cardiotoxic therapies. This has empowered patients, care coordinators and physicians to proactively manage cardiac risks from therapy and we hope these institutional guidelines will be adopted nationally. Citation Format: Brendan Kirwin, Lina Pugliano, Sally Baron Hay. Monitoring for cardiotoxicity in early breast cancer: an Australian experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-17.

Comment on "Chemoradiotherapy Followed by Active Surveillance Versus Standard Esophagectomy for Esophageal Cancer: A Systemic Review and Individual Patient Data Meta-Analysis".

In the March issue of the Annals of Surgery, van der Wilk et al1 published a meta-analysis examining patients with esophageal cancer who had a complete clinical response following chemoradiotherapy. The authors concluded that there was no difference in overall or progression-free survival when comparing active surveillance and esophagectomy for patients who were deemed to have a complete clinical response. Surveillance following complete clinical response is undoubtedly a hot-button topic among clinicians who treat esophageal malignancies. Although we applaud the authors for going the extra mile to obtain individual study data to compile for a larger analysis, we had several important questions regarding the results and conclusions of this study. The main question we should ask ourselves when interpreting these results is whether they are generalizable to the general population of patients with esophageal carcinoma receiving neoadjuvant chemoradiation? Notably, the 7 studies within this analysis included patients treated over a 26-year period and, obviously, this represents a very heterogenous group. There was very little consistency in the chemoradiotherapy treatments utilized among the different studies, and only 1 study utilized a more modern CROSS-trial regimen. Baseline patient and tumor characteristics were not provided for either cohort, making it impossible for us to determine similarities with our own patient population. In addition, the authors did not present any subgroup analysis for overall or progression-free survival regarding tumor histology. We know from the CROSS trial that patients with squamous cell carcinoma typically have greater rates of pathologic complete response compared to those with adenocarcinoma.2 Without stratification, we are unable to tell if the results are similar for both histologic subtypes. The authors do take time within the discussion to point out the bias inherent within their study. However, we feel there should be a greater emphasis regarding this bias before “discuss[ing] an active surveillance strategy with patients” as the authors have suggested. Selection bias cannot be ignored in the current meta-analysis as only one of the 7 included studies involved randomized, nonretrospective data. Clearly there are reasons some patients were deemed unfit or refused surgical resection. Given that the I2 of the meta-analysis for overall survival was 55% (P = 0.037), we can conclude that there was substantial heterogeneity between the included studies. Further analysis of the individual studies included in the meta-analysis does reveal some conflicting results. Jeong et al retrospectively analyzed 154 patients with locally advanced esophageal squamous cell carcinoma.3 They found that trimodal therapy, including chemoradiotherapy and esophagectomy, was associated with improved local recurrence-free survival and disease-free survival when compared to definitive chemoradiation, even in patients with a complete metabolic response on FDG-PET. The lone source of nonretrospective data, a randomized trial published by Park et al, also showed a trend toward improved disease-free survival for patients undergoing esophagectomy opposed to those randomized to observation alone.4 Ultimately, at the crux of any discussion of active surveillance, is our ability to define and detect a complete clinical response. Within the current meta-analysis, the definition of clinical complete response varied between studies as different combinations of radiologic, endoscopic, and pathologic methods were employed. Are we to the point where we can reliably and accurately detect clinical complete response? At best, current diagnostic approaches still miss at least 10% of cases of residual carcinoma following neoadjuvant chemoradiation.5 In the current study, 40% of patients in the active surveillance group developed a locoregional occurrence compared to only 7% in the standard esophagectomy arm. Of the 40% that developed local recurrence, only half underwent salvage esophagectomy. Survival data were not presented for these patients. This is not an inconsequential group when you consider that a majority may have been able to undergo a curative intent operation at the outset. In addition, no data were provided concerning the additional interventions required in patients with local recurrences which we know from existing literature can be substantial (ie, EGDs, dilations, stents, etc). We too are eagerly awaiting the results of the ongoing clinical trials comparing standard surgical resection to active surveillance.6,7 Nevertheless, we are wary of suggesting that the results of retrospective, heavily biased studies should guide clinical practice. There ultimately may be some role for active surveillance among patients with an excellent response to neoadjuvant chemoradiation and who are unfit for an operation. However, it should be stressed that at the present time, “watch and wait” for esophageal cancer is not ready day to day clinical practice outside of the context of a clinical trial. ACKNOWLEDGMENT Conceptualization and planning: Z.E.S., K.M.A., M.K.; Analysis and literature search: Z.E.S.; Drafting of manuscript: Z.E.S., K.M.A., M.K.; Critical revision: Z.E.S., K.M.A., M.K.

Abstract No. 89 Safety, Technical Success, and Clinical Outcomes of Percutaneous Cryoablation of Central Renal Tumors without Pyeloperfusion in 94 Patients

To assess the safety, technical success, and clinical outcomes of percutaneous cryoablation (PCA) without pyeloperfusion in 94 patients with central renal tumors. A single-center retrospective review of all adult patients with a central renal tumor treated by interventional radiology using PCA without pyeloperfusion was approved by the local IRB. Central tumors were defined as those involving the renal sinus fat on pre-procedural cross-sectional imaging. Patient demographics and baseline tumor characteristics including maximal tumor diameter, tumor stage, RENAL nephrometry score, and distance to the nearest critical structure was recorded. Details of the PCA procedure, primary and secondary technical success, rates of local recurrence, adverse events (AEs), cancer-specific survival (CSS), and overall survival (OS) were compiled. Aes were categorized according to SIR criteria. 94 patients (48 females (51%); mean age: 68.2 (range:38-87)) with 94 central renal tumors were included. The mean BMI and Charlson co-morbidity index of the cohort were 33.7 (range:20-56) and 6.9 (range:2-12), respectively. Mean maximal tumor diameter, mean RENAL nephrometry score, and mean distance to the nearest critical structure were 37 mm (range:15-67), 8 (range:4-11), and 9 mm (range:0-29), respectively. 59 tumors (63%) and 35 tumors (37%) were classified as T1a and T1b tumors, respectively. Five patients (5%) underwent embolization of the primary mass prior to PCA. The mean number of probes used during PCA was 2.9 (range:1-8). Primary technical success was achieved in 94% (n = 88) of procedures. Of those that did not achieve primary technical success, three underwent successful repeat PCA (secondary technical success: 97%; n = 91/94). The other three patients were surveilled for residual disease. 24 patients (26%) required hydrodissection during PCA. Six patients (6%) experienced major Aes after PCA including hemorrhage requiring embolization (n = 3), hemorrhage requiring transfusions with admission (n = 2), and perinephric abscess necessitating drain placement (n = 1). 22 patients (23%) experienced minor Aes. Nine patients (10%) experienced local recurrence during the follow-up period. OS was 94% (n = 88/94) while CSS was 98% (n = 92/94). PCA of central renal tumors can achieve high rates of technical and oncologic success with major AE and local recurrence rates comparable to published outcomes of PCA for non-central renal tumors, even without the use of pyeloperfusion.

Early outcomes from lutetium Lu-177 vipivotide tetraxetan treatment in patients selected for therapy with piflufolastat F-18 PET imaging.

191 Background: The Vision trial utilized Ga 68 PSMA 11 imaging to select patients for treatment with Lutetium Lu 177 Vipivotide Tetraxetan. Current guidelines allow not only Ga 68 PSMA 11 PET but also Piflufolastat F 18 PET when selecting patients for Lutetium Lu 177 Vipivotide Tetraxetan but little is published on outcomes to this approach. Methods: Patients were enrolled on an IRB approved managed access protocol and were treated by a single investigator at a single institution. Eligible patients had mCRPC and had received previous treatment with at least one androgen receptor pathway inhibitor and at least one round of taxane based chemotherapy. Baseline imaging, demographics, treatment history, and tumor characteristics were collected. Patients were treated with 7.4 GBq of Lutetium Lu 177 Vipivotide Tetraxetan every 6 weeks for up to six cycles. Adverse events and PSA response were collected. Results: Fourteen patients were enrolled between August 2021 and August 2022. All patients had advanced mCRPC, were heavily pre-treated, and had failed both hormonal as well as chemotherapeutic options. The average number of androgen receptor pathway inhibitor courses for the cohort is 2.4 (range 1-4) and the average number of taxane courses for the cohort is 1.5 (Range 1-3). 11 patients underwent Piflufolastat F 18 PET and 3 patients had Ga 68 PSMA 11 PET. Baseline PSA varied significantly from 2.51 - 961.71 ng/mL. Declines of 50% in PSA were observed in 8/14 patients. 2 patients had greater than 80% PSA reductions. Conclusions: PSA treatment responses were similar to those reported in the Vision trial in this cohort of patients selected with either Piflufolastat F 18 PET or Ga 68 PSMA 11 PET supporting the guideline recommendations. Clinical trial information: NCT04825652 .

Access to care and health care quality metrics in urban versus rural patients (pts) with advanced prostate cancer (aPC).

37 Background: Compared to the urban population, pts in rural areas face healthcare disparities and experience inferior healthcare-related outcomes. Herein we aimed to compare the health care quality metrics and outcomes between pts with aPC from rural versus urban areas treated at a tertiary cancer hospital. Methods: In this IRB approved retrospective study, eligibility criteria were: presence of aPC, treatment at a single center (NCI-Designated Comprehensive Cancer Center (NCI-CCC), between 10/2017 to 9/2021). Rural-urban commuting area (RUCA) codes from the 2010 census /were used to classify the pts’ residences as urban (1-3) or rural (4-10) areas. The straight-line to distance of the pts’ place of residence from our institute was also calculated and included in the analysis. The median household income data were obtained and calculated from “The Michigan Population Studies Center”, based on individual zip codes. Results: A total of 994 pts were eligible and included (83.9% urban vs 16.1% rural). The baseline demographic profile and tumor characteristics were similar between the two groups. The median household income of pts from urban areas was higher by $8604/annum than that from rural areas (p&lt;0.0001). There was no difference between urban versus rural pts in terms of receipt of lines of systemic therapies, clinical trial accrual, and receipt of tumor genomic profiling. No significant difference was found in the median overall survival between the two population (83.7 versus 92.8 months; p=0.14). Conclusions: These hypothesis generating data show that access to quality care, as available in an NCI-CCC can mitigate the disparities in the quality of health care delivery and clinical outcomes in urban versus rural pts with aPC. [Table: see text]

Clinical outcomes after utilization of PSMA PET scans in patients with biochemical recurrent prostate cancer.

57 Background: The optimal management of biochemical recurrent prostate cancer (BCR) remains unknown. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans can visualize micrometastatic disease, thus expanding treatment options for BCR from observation or androgen deprivation therapy (ADT) to potentially include metastasis-directed radiation (XRT) or next-generation hormonal agents (NHA). We aimed to describe how BCR patients were managed after PSMA PET scans and their clinical outcomes. Methods: We performed a retrospective chart review of 262 patients from the University of Michigan’s PSMA PET scan database (825 patients with scans 2017–2021). Patients who received maximal local therapy (defined as XRT alone n=199 or surgery + XRT n=63) are presented. Only patients with BCR and a minimum of 1 year follow-up after scans were included. Baseline patient and tumor characteristics, PSMA PET scan results, first and subsequent therapy delivered after PSMA PET, and prostate-specific antigen (PSA) and standard imaging results post PSMA PET were annotated. Primary endpoint is time from first post-scan therapy (within 6 months of scan) to subsequent therapy. Secondary outcomes include probability of no subsequent therapy in 1 year based on first post-scan therapy and PSMA scan findings and PSMA PET findings and association with Gleason score, PSA at BCR, and time from diagnosis to PSMA scan. Results: Of 262 patients with maximal local therapy, 115 met inclusion criteria. Primary definitive treatment was XRT alone in 58% and surgery + XRT in 42%. Median PSA at time of scan was 4.4 ng/mL, and PSMA PET was positive in 87%. First therapy rendered after PSMA PET included 15% no therapy, 26% XRT only, 28% systemic therapy only (ADT +/- NHA), 27% combination therapy (XRT +/- systemic), and 4% other. Subsequent therapy was given in 26%. The median time from first to subsequent therapy was 41 months in patients who received XRT alone as first therapy and not reached for those with combination XRT + ADT. None of the 33 treated with combination therapy required subsequent therapy in 1 year. Remainder of analyses incomplete due to small sample sizes. Results to be updated by time of symposium. Conclusions: This observational study characterizes longer term clinical outcomes in patients with BCR who undergo various therapies after PSMA PET scans. Data may inform current decision making while prospective clinical trial data is awaited.

A decade of surgical outcomes in a structured lung cancer screening program

ObjectiveLung cancer screening can decrease mortality. The majority of screen-detected cancers are early stage and undergo surgical resection. However, there are little data regarding the outcomes of surgical treatment outside of clinical trials. The purpose of this study was to compare the outcomes of curative resection for screen-detected lung cancers with nonscreened, incidentally detected cancers at an institution with a structured screening program. MethodsPatients undergoing lung cancer curative resection from January 2012 to June 2021 were identified from a prospective database. Baseline patient characteristics, tumor characteristics, and outcomes were compared between cancer detected from screening and cancer detected incidentally. ResultsThere were 199 patients in the incidental group and 82 patients in the screened group. Mean follow-up was 33.3 ± 25 months. The screened group had more African Americans (P = .04), a higher incidence of emphysema (P = .02), less prior cancers (P < .01), and more pack-years smoked (P < .01). The screened group had a smaller size (1.74 vs 2.31 cm, P < .01); however, pathologic stage was similar, with the majority being stage I. Postoperative morbidity, 30-day mortality, and overall and recurrence-free survival were similar between groups. Only 48.7% of the incidental group met current US Preventative Services Task Force screening criteria (age 50-80 years, ≥20 pack-year smoking history). ConclusionsScreen-detected lung cancers have excellent postoperative and long-term outcomes with curative resection, similar to incidentally detected cancers. A large portion of incidentally detected lung cancers do not meet current screening guidelines, which is an opportunity for further refinement of eligibility.

Sick leave and predictive factors for sick leave at 12 months after breast cancer surgery in the randomized controlled physical activity trial (PhysSURG-B)

ObjectiveTo evaluate sick leave 12 months after breast cancer surgery, to analyze the effect of adjuvant chemotherapy and to identify predictive factors for sick leave, based on a randomized controlled trial of a non-supervised physical activity intervention (PhysSURG-B). MethodsSick leave days (for patients age 18–67) were collected from the Swedish Social Insurance Agency, and compared between the intervention and control arm in the trial. A random forest model was used to analyze predictive factors for sick leave, including baseline patient and tumor characteristics as well as patient-reported outcomes measuring quality of life, personality traits, pain, anxiety and depression. ResultsA total of 203 patients were analyzed, and when comparing intervention to control, there was no differences in sick leave days (117 vs 55 days, odds ratio 1.21; 95% CI 0.75–1.96). Adjuvant chemotherapy significantly increased days of sick leave (323 vs 42 days, odds ratio 17.3; 95% CI 9.15–34.2). Factors predicting prolonged sick leave were adjuvant chemotherapy, young age, previous mental health problems and low quality of life (measured as FACT-B score) at baseline. ConclusionA non-supervised physical activity intervention had no effect on sick leave 12 months after surgery. Significantly longer sick leave was seen in patients treated by adjuvant chemotherapy. Factors predicting prolonged sick leave can be recognized at baseline and utilized when designing future interventions.

Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort.

TP53 mutations are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor outcome. The prognostic and predictive relevance of EGFR/TP53 co-mutations in NSCLC is controversial. We analyzed lung tissue specimens from 70 patients with NSCLC using next-generation sequencing to determine EGFR and TP53 status and the association between these status with baseline patient and tumor characteristics, adjuvant treatments, relapse, and progression-free (PFS) and overall survival (OS) after surgical resection. We found the EGFR mutation in 32.9% of patients (20% classical mutations and 12.9% uncommon mutations). TP53 missense mutations occurred in 25.7% and TP53/EGFR co-mutations occurred in 43.5% of patients. Stage after surgical resection was significantly associated with OS (P=0.028). We identified an association between progression-free survival and poor outcome in patients with distant metastases (P=0.007). We found a marginally significant difference in OS between genders (P=0.057) and between mutant and wild type TP53 (P=0.079). In univariate analysis, distant metastases (P=0.027), pathological stage (IIIA-IIIB vs I-II; P=0.028), and TP53 status (borderline significance between wild type and mutant; P=0.079) influenced OS. In multivariable analysis, a significant model for high risk of death and poor OS (P=0.029) selected patients in stage IIIA-IIIB, with relapse and distant metastases, non-responsive to platin-based chemotherapy and erlotinib, with tumors harboring EGFR uncommon mutations, with TP53 mutant, and with EGFR/TP53 co-mutations. Our study suggested that TP53 mutation tends to confer poor survival and a potentially negative predictive effect associated with a non-response to platinum-based chemotherapy and erlotinib in early-stage resected EGFR-mutated NSCLC.

Correlation of TROP-2 expression with clinical–pathological characteristics and outcome in triple-negative breast cancer

Limited data exist regarding the associations between TROP-2 protein expression, clinical–pathological characteristics, and outcome in triple-negative breast cancer (TNBC). TROP-2 expression was determined for patients diagnosed with TNBC between 2000 and 2017 by immunohistochemistry (IHC) (ab227689, Abcam) on whole slide tumor sections, and assessed as continuous and categorical variables (H-score high, 201–300, medium 100–200 and low < 100). We investigated the prognostic value of TROP-2 expression for relapse and survival, associations between TROP-2 expression and baseline patient and tumor characteristics, stromal tumor-infiltrating lymphocytes (sTILs), androgen receptor (AR), standardized mitotic index (SMI) and pathological complete response (pCR, in patients with neoadjuvant chemotherapy) were assessed. We included 685 patients with a median age at diagnosis of 54 years (range 22–90 years). After median follow-up of 9.6 years, 17.5% of patients experienced distant relapse. TROP-2 expression was high, medium and low in 97 (16.5%), 149 (25.3%) and 343 (58.2%) of patients, respectively. The presence of LVI, associated DCIS, nodal involvement, apocrine histology and AR expression were correlated with higher TROP-2 levels. There were no associations between TROP-2 expression and sTILs, time-to-event outcomes, or pCR rate after neoadjuvant chemotherapy. TROP-2 expression is not associated with sTILs level and has no prognostic value in our cohort of stage 1–3 TNBC. However, an association with histotype and AR expression was found, suggesting a histotype specific TROP-2 expression pattern with highest expression in apocrine subtype, warranting further research.

Hepatic Hilar Nerve Block for Adjunctive Analgesia during Percutaneous Thermal Ablation of Hepatic Tumors: A Retrospective Analysis

PurposeTo determine whether hepatic hilar nerve block techniques reduce analgesic and sedation requirements during percutaneous image-guided thermal ablation of hepatic tumors. Materials and MethodsA single-center retrospective cohort analysis was performed of 177 patients (median age, 67 years; range, 33–86 years) who underwent percutaneous image-guided thermal ablation of liver tumors. All patients were treated utilizing local anesthetic and moderate sedation between November 2018 and November 2021 at a tertiary level hospital, with or without the administration of a hepatic hilar nerve block. Univariable and multivariable linear regression analyses were performed to determine the relationship between the administration of the hilar nerve block and fentanyl and midazolam dosages. ResultsA total of 114 (64%) patients received a hilar nerve block in addition to procedural sedation, and 63 (36%) patients received procedural sedation alone. There were no significant differences in the baseline demographic and tumor characteristics between the cohorts. The procedure duration was longer in the hilar block cohort than in the unblocked cohort (median, 95 vs 82 minutes; P = .0012). The technical success rate (98% in both the cohorts, P = .93) and adverse event rate (11% vs 3%, P = .14) were not significantly different between the cohorts. After adjusting for patient and tumor characteristics, ablation modality, and procedure and ablation durations, hilar nerve blocks were associated with lower fentanyl (−18.4%, P = .0045) and midazolam (−22.7%, P = .0007) dosages. ConclusionsHepatic hilar nerve blocks significantly decrease the fentanyl and midazolam requirements during thermal ablation of hepatic tumors, without a significant change in the technical success or adverse event rates.

Results from a Phase I Trial Using Nivolumab in Combination with Dose Adjusted EPOCH in Newly Diagnosed Peripheral T-Cell Lymphomas

Introduction: Dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a first line chemotherapy option for peripheral T-cell lymphomas (PTCLs), but only a minority of patients (pts) are cured. Immune checkpoint blockade (CPB) demonstrated an overall response rate (ORR) of 30% in heavily pre-treated PTCLs in phase I/II studies but rapid or hyperprogression has also been observed in some non-responders. Cytotoxic chemotherapy may be additive to CPB by increasing the expression of neoantigens and therefore overcoming resistance due to weak tumor immunogenicity (Blood Advances. 2021). Methods: We conducted a phase I trial using a flat dose of the anti-PD1 antibody nivolumab (Nivo) in combination with DA-EPOCH in newly diagnosed PTCLs. Pts were allowed to receive one cycle of chemotherapy prior to enrollment. Pts received Nivo (360 mg) followed by DA-EPOCH every 21 days for 6 or 5 cycles (if prior chemotherapy) in the absence of toxicity or lack of efficacy. For immune related adverse event (irAE), Nivo was held until resolution to grade (G)1 and on ≤10 mg prednisone. For any G3 irAE, Nivo was withheld during the subsequent cycle, and if recurrence, Nivo was permanently discontinued. For protocol defined serious G3 irAEs (e.g., pneumonitis) or G4 irAE, Nivo was omitted from remaining cycles. After completing chemotherapy, pts had the option to proceed with autologous stem cell transplant (ASCT). Responses were assessed by PET/CT after 2 cycles of Nivo + DA-EPOCH and after the last cycle, using RECIL criteria. The primary objective was investigator-assessed ORR to Nivo + DA-EPOCH. Secondary objectives included toxicity, event free survival (EFS), progression free survival (PFS), and overall survival (OS). Selected baseline pt and tumor characteristics, as well as targeted next generation sequencing and multiplex immunohistochemistry of diagnostic tumor tissue were assessed and matched to response, EFS, and PFS in an exploratory analysis. Results: Table 1 displays pt characteristics of the 18 pts enrolled. Nine of 18 pts received treatment prior to enrollment as follows: one cycle of anthracycline based chemotherapy (N=6), oral methotrexate (N=1, SPTCL), and systemic steroids (N=2). The EPOCH dose level ranged from -6 to +3 (median dose level -1). All dose level reductions occurred due to G4 thrombocytopenia. In total, 10% (N=8 of 77) of treatment cycles were delayed >3 days; no delays were due to inadequate hematologic recovery. Immune related AEs of all grades occurred in 78% (N=14) of pts and 39% (N=7) of pts experienced ≥ grade 3 irAEs. 44% (N=8) of pts required discontinuation of Nivo due to irAEs. In the 8 pts whose irAEs resulted in discontinuation of Nivo, the irAE occurred prior to the second or third cycle of Nivo + DA-EPOCH. None of the 6 pts who received a cycle of anthracycline based chemotherapy prior to enrolling on trial experienced an irAE that resulted in dose hold or discontinuation of Nivo, whereas 8 of 12 pts who did not receive a prior cycle of anthracycline based chemotherapy experienced an irAE requiring a dose hold or discontinuation of Nivo. Interim and end of induction ORR were 94% (6 CR, 11 PR; 1 (6%) had SD) and 89%, respectively. We observed 11 CR, 5 PR, and 2 PD at the end of induction. Figure 1 displays response to Nivo + DA-EPOCH and duration of response. 2 pts received consolidation with ASCT. The number of doses of Nivo was significantly associated with improved response (CR vs. PR vs. PD); pts who received more doses of Nivo were more likely to achieve CR (p=0.0066). With a median follow up of 707 days (95% CI: 399-962), median EFS is 373 days (95% CI: 214-616), median PFS is 434 days (95% CI: 225-666), and median OS is 714 days (95% CI: 309-NR). Exploratory analyses, including expression of PD-1 and PDL-1 is ongoing. Discussion: As expected, in the entire cohort irAEs were common, often leading to discontinuation of CPB. However, no hyperprogression events were observed and dose-limiting irAEs did not occur in pts who received prior chemotherapy. Pts who were able to receive more Nivo had better efficacy outcomes. Given the high-risk characteristics of this cohort, the observed responses in rare subtypes, the encouraging PFS with a long median follow up, and the acceptable toxicity profile, further investigation of chemoimmunotherapeutic treatment strategies is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preclinical Activity of Allogeneic CS1-Specific CAR T-Cells (UCARTCS1) in Multiple Myeloma

Introduction: The substantial activity of chimeric antigen receptor (CAR) T-cells in multiple myeloma (MM) has recently been shown by the success of BCMA-CAR T-cell therapy. Nevertheless the difficulties in (timely) generation of CART cells for each patient, the limited availability of manufacturing slots, and the frequent BCMAlow MM relapses after therapy urge the investigators to search for i) alternative, "off the shelf", available sources of CAR T-cells and ii) alternative target antigens than BCMA. UCARTCS1 cells are "off the shelf" allogeneic CAR T-cells derived from healthy donors targeting CS1 (SLAMF7), which is a highly attractive target, due to its overexpression on MM cells. Furthermore, the genes coding for the TCRα chain of the TCRab receptor and for CS1 are disrupted in UCARTCS1 cells using Cellectis' TALEN® gene-editing technology. These modifications aim to minimize the potential risk for allo-TCR-mediated graft-versus-host disease (GvHD) upon infusion in patients and diminish CS1-mediated fratricide. In this study, we evaluated the preclinical activity of UCARTCS1 in MM cell lines, in bone marrow (BM) samples obtained from MM patients and in a MM mouse model. We also investigated the potential impact of previous therapy and tumor characteristics on the in vitro efficacy of UCARTCS1. Methods: Luciferase-transduced MM cell lines with different expression levels of CS1 were incubated with UCARTCS1 cells or control (non-transduced CS1/TCRαβ double knock-out) T-cells at different E:T ratios for 24 hours. MM cell lysis was assessed by bioluminescence. Anti-MM activity of UCARTCS1 was also evaluated in 25 BM samples obtained from newly diagnosed (n=10; NDMM), daratumumab-naïve relapsed/refractory patients (n=10; RRMM; median of 3 prior therapies) and from daratumumab-refractory patients (n=5; DRMM; median of 3 prior therapies) in 24-hour flow cytometry-based cytotoxicity assays. The results were correlated to CS1 expression levels of MM cells, Treg frequency, and several other patient characteristics such as treatment history. Results: UCARTCS1 induced strong CS1 CAR-mediated and dose-dependent lysis of different MM cell lines expressing variable levels of CS1 (MM1s, L363, UM9, U266). UCARTCS1 cells also effectively lysed primary MM cells in a dose-dependent and CAR-mediated manner, with a mean maximal lysis of 96.9% (Figure 1). In these BM samples, UCARTCS1 cells also targeted CS1+ non-malignant hematopoietic cells, such as CD4+ T-cells, CD8+ T-cells, B cells, and NK cells, while sparing the CS1low fraction in each cell subset. However, the lysis of normal cells was less efficient than MM cell lysis, which could be explained by substantially lower CS1 expression on normal cells compared to MM cells (Figure 2). CS1 expression on MM cells and UCARTCS1 cytotoxic activity were both comparable in the different patient subgroups. In addition, baseline tumor and immune characteristics, such as the expression level of CS1 on MM cells, the tumor load (MM cell percentage in BM), or frequency of Treg cells in the BM did not affect CAR T-cell mediated cytotoxicity. Finally, UCARTCS1 exhibited durable dose-dependent anti-MM activity in mouse xenograft models after i.v. injection of CAR T-cells compared to mice treated with CAR- control T-cells. Conclusion: UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in a MM xenograft model. There was no difference in activity between heavily pretreated and newly diagnosed patients, indicating that mechanisms of resistance to prior therapies do not result in reduced susceptibility to UCARTCS1-mediated lysis in vitro. UCARTCS1 was also effective in samples from patients with relatively low CS1 expression, with high tumor burden, or with high Treg numbers. These data support the ongoing phase 1 clinical trial with UCARTCS1 in heavily pretreated MM patients (NCT04142619). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

DISP-12. RACIAL DISPARITY IN LENGTH OF STAY FOLLOWING CRANIOTOMY FOR PRIMARY BRAIN GLIOMA

Abstract Introduction The racial disparities of opportunity to receive the appropriate surgical intervention and insurance coverage for adjuvant care may result in surgical outcome and survival disparities among different races. Length of stay (LOS) is an important quality metric measure for determining the distribution of medical resources and their consumption. This study aims to provide a perspective on racial disparities in the overall length of stay and complications for patients undergoing craniotomy for primary brain glioma. METHODS The authors performed a retrospective chart review of all patients who underwent craniotomies for resection of primary brain tumors at the Moffitt Cancer Center from 2004-2018. Patients age, race, tumor type, comorbidities, length of stay and complications were reviewed. RESULTS A total of 701 patients underwent craniotomies for primary brain glioma, but 66 were excluded due to insufficient follow-up or incomplete records. The racial categories include Caucasians, African American, Asian, Hispanic, and other. Due to the prevalence of Caucasians, the minorities groups were pooled as non-Caucasians. Both cohorts were similar in baseline comorbidities, KPS, tumor characteristics, and surgical factors. Mean LOS remained lower for Caucasians versus non-Caucasians (3.6 vs. 5.5 d). The differences in LOS remain among different tumor types, including GBM (4 vs. 6.7 d), anaplastic astrocytoma (2 vs. 4.4 d), and oligodendroglioma (2.3 vs. 3.7 d). Interestingly, among astrocytoma, Caucasians had a longer LOS (3 vs 1.2 d). CONCLUSION Our results highlight disparate treatment patterns that reflect in LOS among patients undergoing craniotomies for primary brain gliomas. These findings warrant further investigation regarding current health-care practices and policies.

Comparison of single-port and multi-port Retzius-sparing robot-assisted laparoscopic prostatectomy.

Dissemination of robotic surgical technology for robot-assisted laparoscopic prostatectomy (RALP) has yielded advancements including the Retzius-sparing (RS) approach and the single-port (SP) platform. The safety and feasibility of each individual advancement have been evaluated, yet there is a lack of literature comparing SP RS-RALP to conventional multi-port (MP) RS-RALP. All patients who underwent RS-RALP at our institution between January 2019 and February 2021 were retrospectively reviewed. Data regarding baseline patient and tumor characteristics, operative characteristics, and surgical outcomes were collected and analyzed using the Fisher's exact test and two-tailed unpaired t tests. 62 patients were evaluated: 31 received SP RS-RALP and 31 received MP RS-RALP. Differences in patient age, BMI, and initial PSA were not observed. Lower median lymph node yield (SP: 4 vs MP: 12, p < 0.01), lower estimated blood loss (SP: 111.2 vs. MP 157.8mL, p < 0.01), shorter operative time (SP: 207.7 vs. MP: 255.9min, p < 0.01) and decreased length of stay (SP: 0.39 vs. MP: 1.23days, p < 0.01) were observed in the SP RS-RALP cohort. No differences in positive surgical margins, complications, or biochemical recurrence rates were observed. SP RS-RALP is non-inferior to MP RS-RALP in terms of both perioperative and early oncologic outcomes. Despite the small sample size, the SP platform is a safe and feasible option for RS-RALP and confers potential benefits in the form of shorter operative time and reduced length of stay.