Disease-free Interval Research Articles

Abstract P1-11-04: Assessing the clinico-pathological characteristics of HER2 positive metastatic breast cancer patients experiencing radiologic complete response in a nationwide cohort

Abstract Background: Up to 6% of patients (pts) with HER2 positive (pos) metastatic breast cancer (MBC) experience a radiologic complete response (rCR) to a first line of therapy, but these results mostly derive from dated and/or limited cohorts. Aim of this study was to define the clinico-pathological characteristics of HER2 positive (pos) MBC pts experiencing a rCR. Methods: Pts were selected from the database of the GIM14 study (NCT02284581) and classified according to the best radiologic response obtained to the first line chemotherapy (CT) and upon time-to-treatment-failure (TTF). rCR was defined as complete response (CR) with a TTF > 3 months. The association across variables was tested through logistic regression and their prognostic impact in terms of overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 3,423 pts included in the GIM14 study, 814 had HER2 pos MBC. After exclusion of pts treated with first line endocrine therapy and/or with TTF < 3 months, 656 pts were included in the present analysis, of which 96 (14.6%) experienced a rCR. Instead, the best response was a partial response for 295 pts (45.0%), stable disease for 221 pts (33.7%), and progression for 44 pts (6.7%). Most pts (59.8%) presented de novo MBC; 379 pts (57.8%) had visceral metastases (mets), 609 pts (92.8%) did not have central nervous system (CNS) involvement and 318 pts (48.5%) had only 1 site of distant mets. Also, 445 pts (67.9%) had hormone receptor (HR) pos disease, a HER2 3+ score at immunohistochemistry (IHC) was present in 59.8% of cases versus 40.2% with HER2 2+ at IHC and in situ hybridization (ISH) + disease. Taxanes were the main CT backbone (489 pts, 74.5%), 341 pts (52.0%) had received a Trastuzumab-Pertuzumab doublet. At multivariable analysis, higher odds of experiencing a rCR were reported for presence of non-visceral mets (OR 1.87, 95%CI 1.10-3.17), low number of metastatic sites (OR 2.42, 95%CI 0.80-7.33 for 1 site only) and HER2 3+ score at IHC (OR 1.80, 95%CI 1.09-2.98). Disease-free interval (DFI) was associated to rCR at univariable but not at multivariable analysis. HR status, CT backbone and type of anti-HER2 regimen were not associated with rCR neither at univariable nor at multivariable analysis. Median follow-up was 76.2 months. Amongst pts with TTF>12 months, those with rCR had a significantly higher OS compared to those not experiencing a rCR (median OS 133 and 90 months, respectively; p=0.0191). OS rates in pts with TTF ≥ 12 months were 97.8% at 2-year follow-up and 59.4% at 5-year follow-up. Instead, in pts with TTF ≥ 60 months, OS rates were 76.7% at 10-year follow-up. Amongst the 96 pts experiencing a CR, 38 had a rCR with TTF between 12 and 60 months, while 22 pts had a rCR with a TTF ≥ 60 months. The remaining pts had a CR with a TTF < 12 months. Pts with HR negative (neg) disease were found to be more likely to experience a rCR with a with TTF between 12 and 60 months, whilst pts with HR pos disease had a higher probability to experience a rCR with a TTF ≥ 60 months (p=0.0074). Pts with HER2 3+ score at IHC had a higher probability to achieve a rCR with a TTF ≥ 12 months compared to pts with HER2 2+ score at IHC and ISH + (p=0.0216). Age at diagnosis, menopausal status, DFI, number and site of mets, CT backbone and anti-HER2 therapy did not influence the duration of the rCR obtained. Conclusions: This study characterized a real-world cohort of HER2 positive MBC patients experiencing radiologic complete response to a first line treatment. Based on these results a clinical trial focused on liquid biopsy-based minimal residual disease is being designed. Novel anti-HER2 agents are gaining momentum as ever increasingly effective treatments and future de-escalation strategies after complete response will represent a growing need. Citation Format: Linda Cucciniello, Eva Blondeaux, Claudia Bighin, Simona Gasparro, Stefania Russo, Arianna Dri, Palma Pugliese, Andrea Fontana, Giuseppe Naso, Antonella Ferzi, Ferdinando Riccardi, Valentina Sini, Luca Boni, Alessandra Fabi, Filippo Montemurro, Michelino De Laurentiis, Grazia Arpino, Lucia Del Mastro, Lorenzo Gerratana, Fabio Puglisi. Assessing the clinico-pathological characteristics of HER2 positive metastatic breast cancer patients experiencing radiologic complete response in a nationwide cohort [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 P1-11-04.

Abstract P3-05-38: Biology and clinical course of lobular cancer in breast cancer (BC)

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 10–15% of all breast cancers. Due to its distinctive growth pattern and biology, lobular carcinoma often fails to form distinct masses that can be easily detected by palpation or mammography. Because it is substantially less common than infiltrating ductal carcinoma (IDC), knowledge about clinical outcomes of ILC has been based on studies including relatively small patient (pt) numbers. Thus, we sought to assess the biologic and genomic features of ILC in the context of clinical outcomes. Methods: Eligible pts were adults with metastatic lobular or ductal BC seen at MD Anderson between 1997 and 2020. Overall survival (OS), progression-free survival (PFS), and disease-free interval (DFI) from the initial diagnosis were estimated using the Kaplan-Meier method. Survival distributions were compared using the log-rank test. Multivariate Cox proportional hazards regression models were applied to assess effect of covariates of interest on OS and DFS. No statistical adjustment was made for multiple testing. Results: A total of 7642 IDC and 1159 ILC female metastatic BC pts were included in the analysis. Clinical characteristics are presented in the table. Pts with ILC were on average older, had fewer metastases, and were more likely to have a family history of breast or ovarian cancer than pts with IDC. Lobular cases were less likely to be HER2+, had lower Ki-67, and lower nuclear grade than ductal cancer cases. The median follow-up was 4.37 years. The median OS for all pts from initial diagnosis was 5.38 years; 5.21 years and 6.57 years for IDC and ILC, respectively. ER positivity was associated with longer OS in both IDC [Hazard ratio (HR) 0.47, 95% confidence interval (CI): 0.45 - 0.49, P< 0.0001] and ILC (HR 0.63, 95% CI: 0.54 - 0.75, P< 0.0001). In de novo metastatic disease, the median OS was 3.74 years in IDC and 4.15 years in ILC. In recurrent IDC and ILC, the median OS was 5.84 and 7.89 years, respectively. De novo presentation had better OS from time of metastatic disease diagnosis for pts with both ILC and IDC than those presenting with recurrent cancer; however, de novo presentation was associated with worse PFS on 1st line therapy. In ILC, grade III had a poorer prognosis than grade I/II; (HR 1.47, 95% CI: 1.30 - 1.68, P< 0:0001). Among pts with IDC, grade I had the best outcomes, followed by grade II, then grade III. In IDC, significantly improved OS was observed in HER2+ BC (HR 0.85, 95% CI: 0.79 - 0.92), P< 0:0001). The median PFS for all pts was 0.53 years and the median DFI was 2.61 years. In both ILC and IDC, PFS and DFI were better in cancers that were ER+ or grade I/II. Conclusions: In metastatic BC pts, the biologic phenotypes and clinical behavior of ILC and IDC differ. More complete and reliable characterization of ILC may yield useful information regarding the biologic nature of ILC resulting in discovery of actionable findings leading to more personalized therapy. Further analyses of genomic features and patterns of metastatic sites between IDC and ILC will be presented. Patient characteristics of ILC and IDC Citation Format: Akshara Singareeka Raghavendra, Roland Bassett, Jason Mouabbi, Rachel M. Layman, Debu Tripathy. Biology and clinical course of lobular cancer in breast cancer (BC) [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 P3-05-38.

Abstract P3-05-53: IMPACT OF THE BODY MASS INDEX (BMI) ON THE SURVIVAL OF BREAST CANCER WOMEN WHO ACHIEVED A COMPLETE PATHOLOGICAL RESPONSE (pCR) AFTER NEOADJUVANT CHEMOTHERAPY (NACT) IN BRAZIL

Abstract Introduction Breast cancer (BC) it is highly prevalent in the world with a significant mortality rate despite advances in systemic therapies. Obesity increases the risk of this cancer specially in post-menopause women and may even affect the prognosis at all ages. Objective To evaluate the impact of BMI on overall (OS) and disease free interval (DFI) of Brazilian women with BC undergoing NACT and who achieved pCR. Methods This is a retrospective study that included patients with confirmed breast cancer clinical stage I to III, age more than 18 years old and complete records that were submitted to NACT. These patients were divided in four groups based on their BMI by the World Health Organization definition BMI < 18,5 kg/m2: underweight; BMI 18,5 to < 25 kg/m2: healthy weight; BMI 25 a < 30 kg/m2: overweight; BMI ≥30kg/m2: obesity. pCR was defined as absent of invasive tumor in the breast or axilla. Student t test or chi-square test were used to analyze the association of each variable between groups with and without pCR. Univariate and multivariate analyzes were used to calculate odds ratios (OR) and 95% of confidence intervals (CI) of the independent variables BMI, age, clinical stage, immunohistochemistry and correlated with pCR (p value < 0.05 was assumed as statistically significant). The study was approved by local ethics committee. Results A total of 1.481 patients from a single reference center between January 2011 to May 2020 were included. The mean age was 50 years and mean BMI was 28,08 (SD 5,59). Most of the patients presented clinical stage III (67,3%) at diagnosis. Invasive carcinoma nonspecial type was the most frequent (95,11%). After NACT 1.138 (76.84%) still had invasive disease and only 343 (23.16%) had pCR. BMI ratio was 1.6% underweight, 30.5% healthy weight, 34.9% overweight and 33.0% obese. Regarding survival analyses, there was no statistical significance for the different BMI categories for both OS (p=0.43) and DFS (p=0.7) and no statistical significance when evaluated pCR and BMI OS (p=0.26) and DFS (p=0.22). OS was estimated for three groups (healthy weigh: 109 months, overweight: 105 months, obese: 79 months). For patients with underweight, the median OS was not reached. The 5-year OS rate in Brazil, according to this study, was 85.4%. Of these 1,481 women, 387 relapsed after surgery (22 cases: local relapse; 355: systemic relapse; 10: both relapses). Only the underweight reached the median (58 months) but this group is very small, and the other categories still have immature data because the median was not reached to define DFS. The association of the most aggressive subtypes of cancer as predictors of pCR was statistically significant (Luminal B: p=0.019; HER 2: p< 0.001; Triple negative: p< 0.001, in relation to Luminal A). There wasn’t any statistical significance for the different BMI categories. Conclusion This study did not show interference of BMI on OS and/or DFS in Brazilian women with BC undergoing NAC. Few patients reached pCR (23.16%) probably due to the advanced initial stage. On the other hand, pCR was much more frequent in the more aggressive subtypes (Triple negative, HER 2 and Luminal B). Obesity as an independent chronic condition and despite not having an impact on survival in these analyses, most women were overweight or obese (72.85%), showing the frequency of obesity in Brazilian women, which should be understood as a public health problem in the country. In addition, following these women for 10 years can help to understand better the real impact of obesity in breast cancer survival. Table 1. Percentual of breast cancer in different clinical stages. Table 2. Logistic regression considering pCR as an outcome. Citation Format: FERNANDA GRACE BAUk RICHTER, ANDRE MATTAR, Marcelo Antonini, REGINALDO G. COELHO LOPES, Jorge Y. Shida, Luis Henrique Gebrim, Juliana Monte Real. IMPACT OF THE BODY MASS INDEX (BMI) ON THE SURVIVAL OF BREAST CANCER WOMEN WHO ACHIEVED A COMPLETE PATHOLOGICAL RESPONSE (pCR) AFTER NEOADJUVANT CHEMOTHERAPY (NACT) IN BRAZIL [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 P3-05-53.

Abstract HER2-02: HER2-02 HER2-Low Status is Associated with Worse Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer Patients Treated With First-Line Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy

Abstract Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the standard first-line treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (HR+/HER2- aBC). HER2-low BC, which is defined by an IHC score for HER2 of 1+ or 2+ with negative ISH assay, accounts for more than half of all HR+/HER2- aBC cases, and it is associated with remarkable clinical benefit from the novel anti-HER2 antibody drug conjugate (ADC) trastuzumab-deruxtecan. Evidence on the prognostic impact of HER2-low status is controversial in both limited-stage and advanced BC. Here, we sought to investigate the possible prognostic relevance of HER2-low status in a population of aBC patients treated with CDK4/6i plus ET. Methods: We conducted a retrospective-prospective study in six Italian Cancer Centers to investigate the impact of HER2 status (low vs. 0) on the progression-free survival (PFS) and overall survival (OS) of consecutive HR+/HER2- aBC patients treated with CDK4/6i plus ET (aromatase inhibitors or fulvestrant) as a first-line therapy. In the main study analysis, we considered HER2 status in the last tumor assessment (i.e., primary tumor, or, when available, a metastatic lesion). We also performed a subgroup analysis including only patients with HER2 status evaluation in a metastatic lesion collected before CDK4/6i plus ET therapy initiation. The association between HER2 status (low vs. 0) and PFS or OS was evaluated using log-rank test and Cox regression modeling. Results: We evaluated 767 consecutive HR+/HER2- aBC patients treated with CDK4/6i plus ET between January 2017 and January 2022. Of these, 436 patients (56.8%) received CDK4/6i plus ET as a first-line therapy, and they were included in this analysis. Median age was 63 years (range 27-87), and 362 patients (83.0%) were postmenopausal. The majority of patients were treated with palbociclib (68.3%), while 91 (20.9%) and 47 (10.8%) patients received ribociclib and abemaciclib, respectively. Regarding HER2 status, 269 (62.9%) patients had HER2-low tumors, while 159 (37.1%) patients had HER2-0 neoplasms. HER2-low status was associated with significantly lower PFS when compared to HER2-0 status [median PFS (mPFS) 23.6 vs. 32.3 months, respectively; p=0.014]. HER2-low status was also associated with significantly worse OS (mOS 48.7 vs 58.3 months, respectively; p=0.025). These results were confirmed in multivariable models adjusting the impact of HER2 status for clinically-relevant covariates, namely estrogen receptor status, Ki-67, age, number of metastatic sites, presence of liver metastases, disease free interval, ECOG Performance Status. In this analysis, HER2-low status, compared with HER2-0 status, was independently associated with worse PFS [adjusted Hazard Ratio (aHR): 1.62; 95% confidence interval (CI): 1.17-2.24; p< 0.01] and OS (aHR: 1.74; 95% CI: 1.09-2.76; p=0.019). Subgroup analysis conducted in the subset of 256 patients with available metastatic tumor samples collected before CDK4/6i plus ET initiation confirmed that HER2-low status (n=157), when compared to HER2-0 status (n=99), was independently associated with worse PFS (mPFS 24.5 vs 35.2 months, p=0.01; aHR 2.07; 95% CI: 1.28-3.34, p< 0.01) and worse OS (mPFS 48.7 vs 72.3 months, p=0.027; aHR 3.12; 95% CI 1.44-6.77, p< 0.01). Conclusions: This multicenter Italian study revealed that HER2-low status has independent, negative prognostic value in patients with HR+/HER2- aBC treated with CDK4/6i plus ET in the first-line setting. Our results suggest that HER2-low status might be associated with different clinical benefit from standard anticancer therapies in specific clinical settings. The definition of treatment algorithms also taking into account HER2 status is a clinical priority in patients with HR+/HER2- aBC. Citation Format: Emma Zattarin, Caterina Sposetti, Rita Leporati, Luigi Mariani, Alice Menichetti, Chiara Corti, Chiara Benvenuti, Giovanni Fucà, Riccardo Lobefaro, Francesca Ligorio, Daniele Presti, Leonardo Provenzano, Andrea Vingiani, Gaia Griguolo, Marianna Sirico, Ottavia Bernocchi, Antonio Marra, Paola Zagami, Elisa Agostinetto, Flavia Jacobs, Pierluigi Di Mauro, Andrea Esposito, Carlo Alberto Giorgi, Luca Lalli, Laura Boldrini, Pier Paolo Maria Berton Giachetti, Ambra Carnevale Schianca, Valentina Guarneri, Rebecca Pedersini, Agnese Losurdo, Alberto Zambelli, Daniele Giulio Generali, Giuseppe Curigliano, Giancarlo Pruneri, Filippo de Braud, Maria Vittoria Dieci, Claudio Vernieri. HER2-02 HER2-Low Status is Associated with Worse Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer Patients Treated With First-Line Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy [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 HER2-02.

Intensification of Local Therapy With High Dose Rate, Intraoperative Radiation Therapy (HDR-IORT) and Extended Resection for Locally Advanced and Recurrent Colorectal Cancer

BackgroundWe report our long-term experience with high dose rate intraoperative radiotherapy (HDR-IORT) in a single, quaternary institution. Patients/MethodsFrom 2004 to 2020, 60 HDR-IORT procedures for locally advanced colorectal cancer (LACC) and 81 for locally recurrent colorectal cancer (LRCC) were done in our institution. Preoperative radiotherapy was done prior to majority of the resections (89%, 125/141). Sixty-nine percent (58/84) of the resections involving pelvic exenterations had >3 en bloc organs resected. HDR-IORT was delivered using a Freiburg applicator. A single 10 Gy fraction was delivered. Margin status was R0 and R1 in 54% (76/141) and 46% (65/141) of the resections, respectively. ResultsWith a median follow-up time of 4 years, 3-, 5-, and 7- year, overall survival (OS) rates were 84%, 58%, and 58% for LACC and 68%, 41%, and 37% for LRCC, respectively. Local progression-free survival (LPFS) rates were 97%, 93%, and 93% for LACC and 80%, 80%, 80% for LRCC, respectively. For the LRCC group, an R1 resection was associated with worse OS, LPFS, and progression-free survival (PFS), preoperative EBRT was associated with improved LPFS and PFS, and ≥2 years disease-free interval was associated with improved PFS. The most common severe adverse events were postoperative abscess (n = 25) and bowel obstruction (n = 11). There were 68 grade 3 to 4 and no grade 5 adverse events. ConclusionsFavorable OS and LPFS can be achieved for LACC and LRCC with intensive local therapy. In patients with risk factors for poorer outcomes, optimization of EBRT and IORT, surgical resection, and systemic therapy are required.

Abstract GS1-10: Primary results from the randomized Phase II RIGHT Choice trial of premenopausal patients with aggressive HR+/HER2− advanced breast cancer treated with ribociclib + endocrine therapy vs physician’s choice combination chemotherapy

Abstract Background: Combination chemotherapy (CT) remains a standard of care in advanced breast cancer (ABC) with aggressive disease features (rapidly progressing or highly symptomatic disease, including life-threatening visceral crisis). To date, no data have been published on a head-to-head comparison of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) vs combination CT in this patient (pt) population. RIGHT Choice, a randomized, open-label, multi-national, Phase II trial, investigated the efficacy and safety of first-line ribociclib (RIB) + ET vs combination CT in pre/perimenopausal pts with HR+/HER2− ABC with aggressive disease (where combination CT is clinically indicated by physician’s judgment). Here we report the results of the primary endpoint of progression-free survival (PFS) and key secondary endpoints from this study. Methods: Pre/perimenopausal pts with HR+/HER2− ABC (>10% estrogen receptor–positive [ER+]) and no prior systemic therapy for ABC were randomized 1:1 to receive either RIB (600 mg daily, 3 weeks on/1 week off) with letrozole/anastrozole + goserelin or investigator’s choice of CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Randomization was stratified by presence of liver metastases and whether the disease-free interval (duration from date of complete tumor resection for primary breast cancer lesion to the date of documented disease recurrence) was less than two years. Pts included in the trial had ABC not amenable to curative therapy for which combination CT was clinically indicated by physician’s judgment (i.e., symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic non-visceral disease). Median PFS (mPFS) and median time to treatment failure (mTTF) were evaluated by Kaplan-Meier methods. Overall response rate (ORR) was also analyzed, with quality of life and biomarker analyses planned. RIGHT Choice is registered at ClinicalTrials.gov (NCT03839823). Results: A total of 222 pts (112 RIB + ET; 110 CT) were enrolled from Feb 2019 to Nov 2021. Pts with symptomatic visceral metastases (n=150; 67.6%), rapid disease progression (n=41; 18.5%), and markedly symptomatic non-visceral metastases (n=31; 14.0%) were included. Overall, 116 pts (52.3%) had visceral crisis based on guideline definitions. A majority of pts (n=190; 85.6%) had tumors that were ≥50% ER+. At data cutoff (Apr 12, 2022), median follow-up was 24.1 mo; 45.5% and 23.6% of pts remained on treatment in the RIB + ET arm and combination CT arm, respectively. The primary endpoint was met, with a statistically significant PFS benefit of ≈1 year for RIB + ET vs combination CT (mPFS, 24.0 vs 12.3 mo; hazard ratio, 0.54; 95% CI, 0.36-0.79; P=.0007). OS data were immature at data cutoff. The mTTF was ≈10 mo longer for RIB + ET vs CT (18.6 vs 8.5 mo; hazard ratio, 0.45; 95% CI, 0.32-0.63). The ORR was similar for RIB + ET vs CT (65.2% vs 60.0%). No new safety signals were observed in pts on RIB. Lower rates of treatment-related serious adverse events (AEs; 1.8% vs 8.0%) and lower rates of discontinuation due to treatment-related AEs (7.1% vs 23.0%) were seen with RIB + ET vs CT, respectively. AEs observed with combination CT were consistent with the published data. Conclusions: This analysis demonstrated a statistically significant and clinically meaningful PFS benefit with RIB + ET over combination CT in the first-line pre/perimenopausal pt population with aggressive HR+/HER2− ABC disease. This is the first study comparing a CDK4/6i + ET vs combination CT and demonstrating the superiority of RIB + ET in aggressive HR+/HER2− ABC. This evidence supports RIB+ ET use as a preferred option for this pt population. Citation Format: Yen-Shen Lu, Eznal Izwadi Bin Mohd Mahidin, Hamdy Azim, Yeşim ERALP, Yoon-Sim Yap, Seock-Ah Im, Julie Rihani, James Bowles, Teresa Delgar Alfaro, Jiwen Wu, Melissa Gao, Khemaies Slimane, Nagi El Saghir. Primary results from the randomized Phase II RIGHT Choice trial of premenopausal patients with aggressive HR+/HER2− advanced breast cancer treated with ribociclib + endocrine therapy vs physician’s choice combination chemotherapy [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 GS1-10.

Abstract OT2-03-01: heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer

Abstract BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [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 OT2-03-01.

Right Hepatectomy (Réglée) for Liver Metastasis Post Pancreatic Adenocarcinoma – Case Report

Background Metastatic tumors of the liver are the most common hepatic malignant disease, responsible for more than 95% of the total. The size and number of metastases of the liver varies considerably. They maintain the anatomo-pathologic features of the primary cancer, but often are complicated by central necrosis. Pancreatic tumors often metastasize to the liver because of venous drainage to the portal vein. In cases of this occurrence, the disease is considered to be at stage IV with minimal to no consideration for a surgical approach despite the late improvements in liver resection and more efficient chemotherapy. There is a severely limited number of studies for patients undergoing liver resection for liver metastases that arise after a surgical treatment of pancreatic adenocarcinoma. However, these studies, which take in consideration the surgical liver resection versus chemotherapy alone in patients with metachronous metastases of pancreatic cancer demonstrate a significantly longer survival rate. Case presentation The 65 y/o male patient­­­­­­ was diagnosed one year prior to the current events with an adenocarcinoma of the pancreas tail, for which he underwent the surgical procedure of pancreatic tail resection and splenectomy. Ten months after the surgery he complains of fever and body temperature of 38 - 39°C. Despite taking antibiotics for over a month and a half he has no improvement. He is hospitalized in a febrile state, asthenic and pale skin and mucosa. Following an MRI the diagnosis leans towards a liver metastasis. A right réglée hepatectomy is performed. The patient tolerated the procedure well and was discharged in good health. Discussion Determining the amount of liver parenchyma to be removed is an important decision. Anatomic resections mostly include two or more hepatic segments, whereas non-anatomic resection involves the resection of the metastases with a margin of healthy tissue (segmentectomy). The decision concerning the extent of resection is more relevant for the post-operative chemotherapy in colorectal metastasis, where an effort is made to conserve as much as possible remnant liver tissue. A preoperative chemotherapy allows more patients to be considered resectable, but may damage hepatic function and increase the risk of post-operative liver insufficiency. Conclusion In conclusion, hepatic resection for metastatic non-colorectal non-neuroendocrine tumors is safe and is linked to better outcomes in chosen patients. However primary tumour type and disease-free intervals seem to be important variables. Sometimes, hepatic resection may be the only option offering a potential cure, so it should be considered in some patients with liver metastases of non-colorectal non-neuroendocrine tumors. Keywords: General Surgery, Right Hepatectomy, Liver Metastasis, Pancreatic Adenocarcinoma. DOI: 10.7176/JEP/14-9-07 Publication date: March 31 st 2023

HIF1A overexpression predicts the high lymph node metastasis risk and indicates a poor prognosis in papillary thyroid cancer

ObjectiveTo investigate the value of Hypoxia-inducible factor 1 A (HIF1A) in predicting lymph node metastasis (LNM) stage and clinical outcomes of papillary thyroid cancer (PTC) patients. Materials and methodsThe HIF1A gene expression analysis in PTC was performed by bioinformatics approaches followed by evaluating its protein level using immunohistochemistry analysis. The role of HIF1A in predicting the LNM stage was evaluated by logistic regression analysis, nomogram construction, and receiver operating characteristic (ROC) analysis. We performed survival analyses to determine its prognostic value. Enrichment analysis was conducted, and immune cell infiltration and stromal content were evaluated to examine the underlying mechanism of HIF1A in PTC. ResultsHIF1A transcription and protein levels were significantly high in PTC tissue (P < 0.05). Its overexpression predicted high LNM risk and unfavorable prognosis for PTC patients (P < 0.05). Cox regression analysis revealed HIF1A as an independent prognostic biomarker for the disease-free interval (DFI) (P < 0.01). In addition, HIF1A was positively related to tumor-suppressive immunity but was negatively correlated with anti-tumor immunity. HIF1A upregulation was also associated with increased stromal content. ConclusionsHIF1A overexpression is an independent predictor for worse DFI in PTC. The HIF1A expression may affect the prognosis of PTC patients through immune- and stroma-related pathways. Our study provides new insight into the role of HIF1A in PTC biology and clinical management.

First experience with 224Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study).

Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). With a median time to recurrence of 11-12 months, there is a need for novel therapies. Radspherin® consists of the α-emitting radionuclide radium-224 (224Ra), which has a half-life of 3.6 days and is adsorbed to a suspension of biodegradable calcium carbonate microparticles that are designed to give short-range radiation to the serosal peritoneal surface linings, killing free-floating and/or tumor cell clusters that remain after CRS-HIPEC. A first-in-human phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin® was administered intraperitoneally 2 days after CRS-HIPEC. Dose escalation at increasing activity dose levels of 1-2-4-7-MBq, a split-dose repeated injection, and expansion cohorts were used to evaluate the safety and tolerability of Radspherin®. The aim was to explore the recommended dose and biodistribution using gamma-camera imaging. The results from the planned safety interim analysis after the completion of the dose-limiting toxicity (DLT) period of 30 days are presented. Twenty-three patients were enrolled: 14 in the dose escalation cohort, three in the repeated cohort, and six in the expansion cohort. Of the 23 enrolled patients, seven were men and 16 were women with a median age of 64 years (28-78). Twelve patients had synchronous PM stage IV and 11 patients had metachronous PM [primary stage II; (6) and stage III; (5)], with a disease-free interval of 15 months (3-30). The peritoneal cancer index was median 7 (3-19), operation time was 395 min (194-515), and hospital stay was 12 days (7-37). A total of 68 grade 2 adverse events were reported for 17 patients during the first 30 days; most were considered related to CRS and/or HIPEC. Only six of the TEAEs were evaluated as related to Radspherin®. One TEAE, anastomotic leakage, was reported as grade 3. Accordion ≥3 grade events occurred in a total of four of the 23 patients: reoperation due to anastomotic leaks (two) and drained abscesses (two). No DLT was documented at the 7 MBq dose level that was then defined as the recommended dose. The biodistribution of Radspherin® showed a relatively even peritoneal distribution. All dose levels of Radspherin® were well tolerated, and DLT was not reached. No deaths occurred, and no serious adverse events were considered related to Radspherin®.Clinical Trial Registration: Clinicaltrials.gov, NCT03732781.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe

BackgroundLocal treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. MethodsIn total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%–75%) or consensus (≥75%). ResultsA total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). ConclusionThe OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Abbreviated MRI for Secondary Surveillance of Recurrent Hepatocellular Carcinoma After Presumed Curative Treatment.

Little is known about the performance of abbreviated MRI (AMRI) for secondary surveillance of recurrent hepatocellular carcinoma (HCC) after curative treatment. To evaluate the detection performance of AMRI for secondary surveillance of HCC after curative treatment. Retrospective. A total of 243 patients (183 men and 60 women; median age, 65 years) who underwent secondary surveillance for HCC using gadoxetic acid-enhanced MRI after more than 2 year of disease-free period following curative treatment, including surgical resection or radiofrequencyablation(RFA). A 3.0 T/noncontrast AMRI (NC-AMRI) (T2-weighted fast spin-echo, T1-weighted gradient echo, and diffusion-weighted images), hepatobiliary phase AMRI (HBP-AMRI) (T2-weighted fast spin-echo, diffusion-weighted, and HBP images), and full-sequence MRI ASSESSMENT: Four board-certified radiologists independently reviewed NC-AMRI, HBP-AMRI, and full-sequence MRI sets of each patient for detecting recurrent HCC. Per-lesion sensitivity, per-patient sensitivity and specificity for HCC detection at each set were compared using generalized estimating equation. A total of 42 recurred HCCs were confirmed in the 39 patients. The per-lesion and per-patient sensitivities did not show significant differences among the three image sets for either reviewer (P ≥ 0.358): per-lesion sensitivity: 59.5%-83.3%, 59.5%-85.7%, and 59.5%-83.3%, and per-patient sensitivity: 53.9%-83.3%, 56.4%-85.7%, and 53.9%-83.3% for NC-AMRI, HBP-AMRI, and full-sequence MRI, respectively. Per-lesion pooled sensitivities of NC-AMRI, HBP-AMRI, and full-sequence MRI were 72.6%, 73.2%, and 73.2%, with difference of -0.6% (95% confidence interval: -6.7, 5.5) between NC-AMRI and full-sequence MRI and 0.0% (-6.1, 6.1) between HBP-AMRI and full-sequence MRI. Per-patient specificity was not significantly different among the three image sets for both reviewers (95.6%-97.1%, 95.6%-97.1%, and 97.6%-98.5% for NC-AMRI and HBP-AMRI, respectively; P ≥ 0.117). NC-AMRI and HBP-AMRI showednosignificantdifferenceindetection performance to that of full-sequence gadoxetic acid-enhanced MRI during secondary surveillance for HCC after more than 2-year disease free interval following curative treatment. Based on its good detection performance, short scan time, and lack of contrast agent-associated risks, NC-AMRI is a promising option for the secondary surveillance of HCC. 3. Stage 2.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial

Background and PurposeStereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). MethodsThis single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. Results549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86–0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93–0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69–0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and ‘other’ (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. ConclusionPTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Preoperative prognostic factors for 5-year survival following pulmonary metastasectomy from colorectal cancer: a systematic review and meta-analysis.

We seek to identify preoperative prognostic factors and measure their effect on 5-year survival following pulmonary metastasectomy (PM) for Colorectal Cancer (CRC). We systematically reviewed the databases of Cochrane Library, MEDLINE, Embase and Google Scholar from January 2000 to April 2021 to identify preoperative factors that have been investigated for their prognostic effect on survival following PM. Quality assessment was performed using the QUIPS tool. The prognostic effect of each identified factor on 5-year survival post-PM was estimated using random-effects meta-analyses. We identified 115 eligible articles which included 13294 patients who underwent PM from CRC. The overall 5-year survival after resection of the lung metastasis was 54.1%. The risk of bias of the included studies was at least moderate in 93% (107/115). Seventy-seven preoperative factors had been investigated for their prognostic effect. Our analysis showed that 11 factors had favourable and statistically significant prognostic effect on 5-year survival post-PM. These included solitary metastasis, size <2 cm, unilateral location, N0 thoracic disease, no history of extra-thoracic or liver metastasis, normal carcinoembryonic antigen levels both before PM and CRC excision, no neo-adjuvant chemotherapy before PM, CRC T-stage < T4 and no p53 mutations on CRC. Disease-free interval at 24 months did not appear to affect 5-year survival. Despite the considerable risk of bias in the literature, our study consolidates the available evidence on preoperative prognostic factors for PM from CRC. These findings can complement both clinical practice and the design of future research on the field of PM.

A prognostic score from a multicentric retrospective analysis of patients affected by sarcoma with metachronous lung metastases undergoing metastasectomy.

Despite the lack of evidence-based on prospective randomized studies, surgery has become the cornerstone of the treatment in patients with pulmonary oligometastatic sarcomas. Our study aimed to construct a composite prognostic score for metachronous oligometastatic sarcoma patients. A retrospective analysis was performed on data patients who underwent radical surgery for metachronous metastases in sixresearch institutes from January 2010 to December 2018. The log-hazard ratio (HR) obtained from the Cox model was used to derive weighting factors for a continuous prognostic index designed to identify differential outcome risks. A total of 251 patients were enrolled in the study. In the multivariate analysis, a longer disease-free interval (DFI) and a lower neutrophil-to-lymphocytes ratio (NLR) were predictive of a better overall survival (OS) and disease-free survival (DFS). A prognostic score was developed based on DFI and NLR data, identifying 2 risk class groups for DFS (3-years DFS 20.2% for the high-risk group [HRG]and 46.4% for the low-risk group [LRG] [<0.0001]) and 3 risk groups for OS (3 years OS 53.9% for the HRG vs. 76.9% for the intermediate-risk group and 100% of the LRG (p < 0.0001)). The proposed prognostic score effectively predicts outcomes for patients with lung metachronous oligo-metastases from the surgically treated sarcoma.

Disease-Free Interval and Tumor Stage Complementarily Predict the Biological Behavior of Recurrent Hepatocellular Carcinoma.

Currently used treatment algorithms were originally established based on the clinical outcomes of the initial treatment for primary hepatocellular carcinoma (HCC), and no strong evidence exists yet to suggest if these algorithms could also be applicable to patients with recurrent HCC after surgery. As such, this study sought to explore an optimal risk stratification method for cases of recurrent HCC for better clinical management. Among the 1616 patients who underwent curative resection for HCC, the clinical features and survival outcomes of 983 patients who developed recurrence were examined in detail. Multivariate analysis confirmed that both the disease-free interval (DFI) from the previous surgery and tumor stage at recurrence were significant prognostic factors. However, the prognostic impact of DFI seemed different according to the tumor stages at recurrence. While curative-intent treatment showed strong influence on survival [hazard ratio (HR), 0.61; P < 0.001] regardless of the DFI in patients with stage 0 or stage A disease at recurrence, early recurrence (< 6 months) was a poor prognostic marker in patients with stage B disease. The prognosis of patients with stage C disease was exclusively influenced by the tumor distribution or choice of treatment than by the DFI. The DFI complementarily predicts the oncological behavior of recurrent HCC, with its predictive value differing depending on the tumor stage at recurrence. These factors should be considered for selection of the optimal treatment in patients with recurrent HCC after curative-intent surgery.

Factors affecting prognosis in canine subcutaneous mast cell tumors: 45 cases.

To evaluate the clinical outcome of subcutaneous mast cell tumors (SQMCT) and to identify clinical and histological characteristics of more aggressive disease. Retrospective study. Forty-five dogs with 48 SQMCTs. Medical records were reviewed (2011-2021) for patient information, clinical, and histopathological data including multinucleation, necrosis, invasion into local muscle, an infiltrative growth pattern, tumor grade (if listed), mitotic index, and surgical margins. The presence of local recurrence, lymph node metastasis, survival time, and other parameters evaluating patient outcome were also recorded. Local recurrence occurred in 17.8% (8/45) of dogs, 11.1% (5/45) developed metastatic recurrence, and 26.7% (12/45) developed lymph node metastasis. Dogs with lymph node metastases had a median disease-free interval (DFI) of 194 days (18-1864), while median DFI was not reached for dogs without lymph node metastasis (p=.0012). Median survival time for dogs with lymph node metastasis was 551 days (110-2050) compared to 1722 days (10-1722) without metastasis (p=.0432). Local recurrence resulted in a significantly shorter median survival time of 551 days (80-2050) compared to 1722 days (10-1722) for dogs without local recurrence (p=.0038). Dogs with infiltrative tumors had a median DFI of 268 days (3-1722) and DFI for dogs without an infiltrative pattern had not reached median at 1864 days (10-1864) (p=.011). Lymph node metastasis decreased disease-free interval and survival. Subcutaneous mast cell tumors may be a more aggressive disease than previously reported.

ANO4 Expression Is a Potential Prognostic Biomarker in Non-Metastasized Clear Cell Renal Cell Carcinoma.

Background: Over the past decade, transcriptome profiling has elucidated many pivotal pathways involved in oncogenesis. However, a detailed comprehensive map of tumorigenesis remains an enigma to solve. Propelled research has been devoted to investigating the molecular drivers of clear cell renal cell carcinoma (ccRCC). To add another piece to the puzzle, we evaluated the role of anoctamin 4 (ANO4) expression as a potential prognostic biomarker in non-metastasized ccRCC. Methods: A total of 422 ccRCC patients with the corresponding ANO4 expression and clinicopathological data were obtained from The Cancer Genome Atlas Program (TCGA). Differential expression across several clinicopathological variables was performed. The Kaplan-Meier method was used to assess the impact of ANO4 expression on the overall survival (OS), progression-free interval (PFI), disease-free interval (DFI), and disease-specific survival (DSS). Univariate and multivariate Cox logistic regression analyses were conducted to identify independent factors modulating the aforementioned outcomes. Gene set enrichment analysis (GSEA) was used to discern a set of molecular mechanisms involved in the prognostic signature. Tumor immune microenvironment was estimated using xCell. Results: ANO4 expression was upregulated in tumor samples compared to normal kidney tissue. Albeit the latter finding, low ANO4 expression is associated with advanced clinicopathological variables such as tumor grade, stage, and pT. In addition, low ANO4 expression is linked to shorter OS, PFI, and DSS. Multivariate Cox logistic regression analysis identified ANO4 expression as an independent prognostic variable in OS (HR: 1.686, 95% CI: 1.120-2.540, p = 0.012), PFI (HR: 1.727, 95% CI: 1.103-2.704, p = 0.017), and DSS (HR: 2.688, 95% CI: 1.465-4.934, p = 0.001). GSEA identified the following pathways to be enriched within the low ANO4 expression group: epithelial-mesenchymal transition, G2-M checkpoint, E2F targets, estrogen response, apical junction, glycolysis, hypoxia, coagulation, KRAS, complement, p53, myogenesis, and TNF-α signaling via NF-κB pathways. ANO4 expression correlates significantly with monocyte (ρ = -0.1429, p = 0.0033) and mast cell (ρ = 0.1598, p = 0.001) infiltration. Conclusions: In the presented work, low ANO4 expression is portrayed as a potential poor prognostic factor in non-metastasized ccRCC. Further experimental studies should be directed to shed new light on the exact molecular mechanisms involved.

Bioinformatics identify the role of chordin-like 1 in thyroid cancer.

The abnormal expression of chordin-like 1 (CHRDL1) is identified in many cancers, while the effect of CHRDL1 in thyroid cancer (THCA) remains unclear. The University of California Santa Cruz, Gene Expression Profiling Interactive Analysis, University of Alabama at Birmingham Cancer, and Gene Expression Omnibus database (GSE33570, GSE33630, and GSE60542) were used for determining the mRNA and methylation expression of CHRDL1 in tumor and normal tissues. Human Protein Atlas was used for exploring the protein expression level of CHRDL1. The genes correlated to CHRDL1 were assessed by cBioPortal database. The prognostic value of CHRDL1 was evaluated through Kaplan-Meier method, cox regression, and nomogram analysis. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and gene set enrichment analysis were used for predicting potential function of CHRDL1. The relationship between CHRDL1 and immune cell infiltration was determined by Pearson method. The downregulated mRNA and protein expressions of CHRDL1 were identified in THCA through the analysis of data from The Cancer Genome Atlas, Gene Expression Omnibus, and Human Protein Atlas database. The survival analysis showed that the CHRDL1 expression significantly affected disease-free interval (DFI) and progression-free interval, and CHRDL1 was an independent predictor of DFI. Besides, we found that C-C motif chemokine ligand 21 could significantly affect DFI time when it was co-expressed with CHRDL1. Additionally, the function of CHRDL1 was enriched in cell migration, apoptosis, and immune cell receptor. The downregulated expression of CHRDL1 was observed in THCA and caused poor prognosis. CHRDL1 may be involved in signal pathway related to cancer development and immune response, which suggested it could be a potential biomarker.

Trial in progress: A phase 2 study of CTX-009 in adult patients with metastatic colorectal cancer who have received two or three prior systemic chemotherapy regimens.

TPS281 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Patients with unresectable locally advanced and unresectable metastatic colorectal cancer (CRC) are sequentially treated with various combinations or single agent courses of cytotoxic chemotherapy agents including 5-fluorouracil and its orally administered family members (capecitabine, TAS-102) oxaliplatin, and irinotecan, as well with targeted therapies such as bevacizumab or aflibercept (anti-VEGF), cetuximab or panitumumab (anti-EGFR), or multitargeted tyrosine kinase inhibitors (regorafenib). In subsets of patients who have had multigene panel testing done and whose tumors have been identified as having mutations that drive their disease such as defective mismatch repair, HER-2 overexpression, or NTRK fusions specific treatments with respectively PD-1 or PD-L1 inhibitors, traztuzumab or larotrectinib or entrectinib can also be used effectively. Despite the approval of multiple new agents in the past two decades, the goals of therapy are generally palliative although some patients will have long disease-free intervals when they respond to therapy. In the cases of patients whose disease has progressed, or who have not tolerated 2 or 3 prior lines of therapy, the expectation for tumor response with the available treatments are less than 5% and the median overall survival is approximately 6 months (for 3rd line therapy) or less (for 4th line therapy). In a Phase 1 study with CTX-009, responses have been seen in patients with colorectal cancers who were treated in the 4th line setting. Since CTX-009 targets tumor induced neoangiogenesis, and monoclonal antibodies that target vascular endothelial growth factor (VEGF) has been shown to extend the lives of patients with advanced colorectal cancer, testing of CTX-009 in the setting of advanced treatment refractory colorectal cancer is justified. Methods: CTX-009 is being evaluated in an open label study in patients with previously treated metastatic CRC. This study is designed as an adaptive Simon Two Stage study, with approximately 37 patients to be enrolled into Stage 1. If criteria are met to move to Stage 2, an additional 47 patients will be enrolled, for a total of approximately 84 patients. To move to stage 2 of the study, 3 or more Complete or Partial Responses must be confirmed via RECIST 1.1. Patients will be treated in 28-day cycles, with CTX-009 administration on Day 1 and 15. The primary objective of the study is to assess the efficacy of CTX-009, as measured by Overall Response Rate (ORR). The study is currently activating sites with first patient in expected in 2022. Clinical trial information: NCT05513742 .