High Risk Of Disease Recurrence Research Articles

Abstract PO3-08-09: Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer

Abstract Background: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with lower survival and higher risk of disease recurrence. A new subtype of HER2-low BC which has been proposed from several studies demonstrates that HER2-low patients have distinct somatically genetic alterations and clinical outcomes. We have previously reported that HER2-low BC had distinct clinical and somatic mutational feature compared with HER2-zero and HER2-high tumors. We have therefore extended studies by comparing germline mutation expression among these HER2 subgroups. Methods: 530 Chinese women with BC were enrolled in a prospective protocol between May 2021 to March 2023 at Guangdong Provincial People's Hospital. Genomics data was generated from a gene panel that surveys 102 tumor mutations. Germline variants were classified into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB) and benign (B) groups according to the ACMG/AMP Standards and Guidelines. The cohort was divided into three groups based on HER2 status as HER2-zero (n = 107), HER2-low (n = 259), and HER2-high (n = 127) according to immunohistochemistry and/or fluorescence in situ hybridization results. Results: The most common mutated genes were ATM, FANCD2, ATR, BRACA2, RECQL4 and APC. A total of 71 pathogenic or likely pathogenic (P/LP) mutations were identified in 25 cancer susceptibility genes from 64 patients (12.16%). The most frequent mutated P/LP genes are BRCA2, BRCA1, PALB2, PMS2, MUTYH and PTEN in the HER2-low group; BRCA2, BRCA1 and PALB2 in the HER2-zero cohort; Interestingly, among the nine HER2-high patients, we detected unique P/LP genes in each sample including MRE11, FANCM, ATM, FLCN, NTRK1, TP53, BRCA1, CHEKE2 and FANCA. In addition to P/LP mutations, 751 variants of uncertain significance (VUS) in 95 cancer susceptibility genes were also detected in 361 patients (68.11%). The most frequent mutated VUS mutations occurred genes are FANCD2, ATM, RECQL4, RAD54B and ATR in HER2-low group; ATM, FANCA, POLE, MSH2 and FANCD2 in HER2-zero cohort; and ATM, BRCA2, RECQL4, POLE, FANCI and FANCM for HER2-high patients. Most of mutated genes were homologous recombination repair (HRR) or DNA damage repair (DDR) pathway related genes. Several genes were differentially altered across HER2 subgroups, including the mutation frequency of the BMPR1A (p=0.0344), MSH2 (p=0.0103), and RAD51C (p=0.0336) genes that were significantly higher in HER2-zero group. It’s worth noting that RAD51C was only mutated in HER2-zero subgroup. BMPR1A and MSH2 were also mutated in HER2-low patients. Differentially mutated genes in specific HER2 subgroups may contribute to better research and choice of future therapeutic approaches. In 115 patients who received neoadjuvant therapy and 84 of them were evaluable for pathological response data, HER2-low patients had lower pathological complete response (pCR) rates than HER2-zero and HER2-high subgroups (p=0.0008). In particular, DDR pathway gene ERCC1 have significantly higher mutation frequency in pCR patients (p=0.0115). Conclusion: HER2-low BC patients have distinct germline mutational signatures and differential clinical outcomes under neoadjuvant systemic therapy. These results have provided additional evidence that HER2-low patients comprise a fourth subtype of BC that needs to be accounted for separately in terms of clinical treatment and outcome reporting. Keywords: breast cancer, germline mutations, human epidermal growth factor receptor 2 (HER2), HER2-low, targeted therapy, next-generation sequencing Table 1. List of most frequent mutated genes in HER2-zero, HER2-low and HER2-high groups Citation Format: Ning Liao, Weiqi Zhang, Liangqiu Liu, Wendy Wu, Siqi Wang, Li Cao, Jianguo Lai, Xueying Zhang, Airong Yang, Yulei Wang, Cheukfai Li, Guochun Zhang, Chongyang Ren, Lingzhu Wen. Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-09.

Abstract PO3-02-01: Educational Opportunities to Improve Community Healthcare Professionals’ Management of High-Risk HR-Positive/HER2-Negative Early Breast Cancer

Abstract Background: The treatment landscape for patients with hormone receptor–positive/HER2-negative early breast cancer (HR+/HER2- EBC) has evolved with the emergence of adjuvant CDK4/6 inhibitor therapy as a new option for patients with a high risk of disease recurrence. Adjuvant abemaciclib plus aromatase inhibitors (AIs) is guideline recommended for high clinical risk HR+ disease and reduces risk of recurrence regardless of Ki-67 expression level. Here, we examine healthcare professionals’ (HCPs’) awareness and practice regarding the use of adjuvant abemaciclib. Methods: Between November 2022 and June 2023, we conducted a series of regional educational activities for HCPs focused on management of high-risk HR+/HER2- EBC. Each activity included an interactive lecture led by a clinical investigator with expertise in managing patients with high-risk HR+/HER2- EBC and polling questions designed to assess key aspects of HCP knowledge and practice in the optimal management of high-risk HR+/HER2- EBC. A wider HCP audience was able to view an interactive on-demand webcast with the same content and embedded polling questions. Results: In total, 701 HCPs participated in one of 20 live (n = 373) activities or the one associated on-demand (n = 328) webcast. The distribution of HCP participation differed between the live and online activities with more physicians participating in the online activity vs the live activity (59% vs 34%, respectively); the converse was true for nurse participation (9% online vs 34% live). Polling result trends were similar between the live and online activities. At baseline, 38% (n/N = 182/405) of HCPs chose adjuvant therapy with an AI plus abemaciclib for a patient with high-risk, node-positive HR+/HER2- EBC consistent with expert and guideline recommendations. Following the education, 92% (n/N = 405/439) of HCPs selected AI plus abemaciclib for appropriate patients. Before education, 32% of HCPs (n/N = 147/454) were aware that adjuvant abemaciclib plus endocrine therapy improved invasive disease-free survival compared with endocrine therapy alone in patients with high-risk, node-positive HR+/HER2- EBC regardless of Ki-67 expression level, which increased to 87% (n/N = 370/425) following the education. Regarding the management of grade 2 neutropenia associated with adjuvant abemaciclib therapy, HCP knowledge was low at baseline (32%, n/N = 141/446) and improved to 80% (n/N = 332/415) after education. Conclusions: HCPs’ knowledge of and practice concerning adjuvant abemaciclib as a newer approved therapy for patients with high-risk HR+/HER2- EBC remain suboptimal. These results suggest an ongoing need for expert guidance and educational activities on the use of adjuvant abemaciclib therapy for appropriate patients with high-risk HR+/HER2- EBC. As the treatment landscape for HR+/HER2- EBC continues to evolve with the potential approval of additional new therapies, this need will only increase with a clear impact on optimizing and individualizing adjuvant therapy strategies for patients with HR+/HER2- EBC. Citation Format: Marie Becker, Timothy Quill, Erika Hamilton, Joyce O'Shaughnessy. Educational Opportunities to Improve Community Healthcare Professionals’ Management of High-Risk HR-Positive/HER2-Negative Early Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-01.

Abstract PO2-13-07: SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT

Abstract Objectives/Rationale: Triple-negative breast cancer (TNBC) patients with residual disease (RD) after neoadjuvant systemic therapy (NAST) are at high risk for disease recurrence and death. While multiple prognostic biomarkers associated with response to NAST have been identified, adaptive resistance mechanisms to NAST remain poorly understood. Identifying and characterizing adaptive resistance mechanisms can illuminate novel therapeutic approaches and improve outcomes for TNBC patients with RD. Methods: Total RNA was isolated from pre-treatment and paired surgical specimens (for patients with RD) from TNBC patients treated with chemotherapy on the NeoSTOP (NCT02413320) or chemoimmunotherapy on the NeoPACT (NCT03639948) neoadjuvant trials and was subjected to RNA exome sequencing. Comparative marker selection analysis was performed by computing the two-sided paired samples t-test for each gene followed by pre-ranked gene set enrichment analysis (GSEA) amongst 23,797 annotated gene sets. Gene sets with false-discovery rate (FDR) corrected P values < 0.001 were determined to be significant. Results: Pre-treatment sequencing data were available for N=200 patients and the overall pathologic complete response (pCR) rate was 56.5%. Paired pre- and post-treatment sequencing data were available for N=58 patients with RD (N=27 from NeoSTOP and N=31 from NeoPACT). 165/23,797 gene sets were significantly enriched in post-treatment compared to pre-treatment samples. SHEN_SMARCA2_TARGETS_UP (M29) was among the top five significantly enriched gene set and was selected for further analysis based on the known role of the SWI/SNF complex in cell survival and the availability of clinically viable SMARCA2 degraders. Pre-treatment SMARCA4 expression was associated with pCR, with lower median expression noted in patients with RD compared to patients who achieved pCR (P=0.04). Pre-treatment SMARCA2 expression was not associated with pCR (P=0.48). On paired sample analysis there was pronounced downregulation of SMARCA4 in post-treatment compared to pre-treatment samples in all patients (mean Z=-1.46, P< 0.0001), in patients treated with chemotherapy (mean Z=-1.65, P< 0.0001), and in patients treated with chemoimmunotherapy (mean Z=-1.28, P< 0.0001). Although there was no difference in SMARCA2 expression between paired pre- and post-treatment samples (mean Z=0.03, P=0.83), there was enrichment of SMARCA2 target expression on GSEA analysis (NES=2.63, FDR q< 0.00001) indicating that SMARCA2 activity is compensating for therapy-induced SMARCA4 loss. Conclusions: We identified 165 gene sets that were significantly enriched in paired post-treatment compared to pre-treatment TNBC samples. Altered activity of the SMARCA2 subunit of the SWI/SNF chromatin remodeling complex was identified as one of the top hits. SMARCA2 and SMARCA4 are mutually exclusive subunits of SWI/SNF, and inactivation of both SMARCA2 and SMARCA4 is synthetic lethal. We observed an association of lower pre-treatment SMARCA4 expression with resistance to NAST and pronounced therapy-induced downregulation of SMARCA4 and induction of SMARCA2 target genes in post-treatment compared to pre-treatment samples, suggesting that SMARCA2 compensates for adaptive SMARCA4 loss. SMARCA2 degraders are in early-phase clinical trials and are known to induce synthetic lethality in SMARCA4-deficient cells. Our results identify adaptive loss of SMARCA4 and synthetic lethal targeting of compensatory SMARCA2 as an attractive therapeutic target in TNBC patients with RD after neoadjuvant chemotherapy or chemoimmunotherapy. Citation Format: Shane Stecklein, Rachel Yoder, Joshua Staley, Zachary Schmitt, Anne O'Dea, Lauren Nye, Deepti Satelli, Gregory Crane, Rashna Madan, Maura O'Neil, Andrew Godwin, Harsh Pathak, Qamar Khan, Joyce O'Shaughnessy, Priyanka Sharma. SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-07.

Investigating locations of recurrences with MRI after CRS-HIPEC for colorectal peritoneal metastases

PurposePatients with colorectal peritoneal metastases (PM) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are at high risk of recurrent disease. Understanding where and why recurrences occur is the first step in finding solutions to reduce recurrence rates. Although diffusion-weighted (DW) MRI is not routinely used in the follow-up of CRC patients, it has a clear advantage over CT in detecting the location and spread of (recurrent) PM. This study aimed to identify common locations of recurrence in CRC patients after CRS-HIPEC with MRI. MethodThis was a single-centre retrospective study of patients with recurrent PM after CRS-HIPEC performed between January 2016 and August 2020. Patients were eligible for inclusion if they had both an MRI preoperatively (MRI1) and at the time of recurrent disease (MRI2). Two abdominal radiologists reviewed in consensus and categorized recurrences according to their location on MRI2 and in correlation with previous disease location on prior imaging (MRI1) and the surgical report of the CRS-HIPEC. ResultsThirty patients were included, with a median surgical PCI of 7 (range 3–21) at the time of primary CRS-HIPEC. In total, 68 recurrent metastases were detected on MRI2, of which 14 were extra-peritoneal. Of the remaining 54 PM, 42 (78%) occurred where the peritoneum was damaged due to earlier resections or other surgical procedures (e.g. inserted surgical abdominal drains). Most recurrent metastases were found in the mesentery, lower abdomen/pelvis and abdominal wall (87%). ConclusionsMost recurrent PMs appeared in the mesentery, lower abdomen/pelvis and abdominal wall, especially where the peritoneum was previously damaged.

Late-onset lymphopenia during radiation is associated with an increased risk of tumor recurrence in newly diagnosed pediatric medulloblastoma.

Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve. We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p=.016; Cox p=.03) and Week 5 (log-rank p=.024; Cox p=.032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p=.04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT. Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.

It Is What the Surgeon Does Not See That Kills the Patient.

Patients with colon cancer may present at multiple different stages of the disease process. Many patients can be cured of colon cancer as a result of a simple surgical procedure usually performed by minimally invasive techniques. However, there are a variable number of patients, estimated at approximately 10%, who have a more advanced disease. If these patients are treated by the current conventional standard of care, the likelihood for treatment failure is extremely high. These are not patients with known disseminated disease but patients who are at high risk of recurrent disease unless special treatments are initiated preoperatively and intraoperatively. The identification of these patients is by (1) a high-quality CT scan, (2) tumor markers found preoperatively, (3) colonoscopic findings, and (4) symptoms. Patients identified as being at high risk require special preoperative treatments which include neoadjuvant chemotherapy. Intraoperative chemotherapy with HIPEC should occur as part of the treatment if peritoneal metastases are documented by biopsy. In the operating room, a thorough exploration of all possible occult peritoneal spaces for metastatic disease needs to be performed. A modified cytoreductive surgical procedure along with a colon resection is performed in order to minimize sites of occult peritoneal metastases. This includes the greater omentum, ovaries, and tubes in postmenopausal women. Peritonectomy is used to create a shroud around the tumor so that all peritoneum that has been in direct contact with the tumor surface is resected and is used as a barrier against tumor cell dissemination in the process of colon cancer resection. If peritoneal metastases are visualized at any site, HIPEC should be included as part of the treatment package. I am convinced that patients at high risk of recurrence will have an improved outcome with proper preoperative evaluation, preoperative neoadjuvant chemotherapy, and a revised intraoperative management strategy.

CtDNA as an Adjunct to Posttreatment PET for Head and Neck Cancer Recurrence Risk Assessment.

Circulating tumor DNA (ctDNA) detection is an emerging technique that identifies minimal residual disease in patients with solid tumors. ctDNA can act as an adjunct method to help overcome the limitations of positron emission tomography (PET) and select patients who are at high risk for recurrence. Retrospective Single Institutional Study. University Hospital Setting. Twenty-nine patients who underwent definitive treatment for squamous cell carcinoma of the head and neck (HNSCC) from 8/2021 to 01/2023 had ctDNA levels analyzed at 1 to 3, 6, 9, and 12 months after definitive treatment. A personalized, tumor-informed, multiplex polymerase chain reaction (PCR) next-generation sequencing (NGS) assay was used to detect the ctDNA levels. The primary outcome was recurrence-free probability (RFP), and the secondary outcomes were overall survival (OS), sensitivity, specificity, and the test's negative (NPV) and positive predictive values (PPV). The median age of patients was 65 years (interquartile range: 56-69), with majority being males (n = 22, 76%). The primary sites were larynx (n = 12), oropharynx (n = 10), and oral cavity (n = 6). Posttreatment ctDNA was detected in 7 patients, all of whom had disease recurrence. ctDNA detection after definitive treatment was associated with a higher risk of disease recurrence (hazard ratio: 9.94, 95% confidence interval: 1.56-63.3, P = .015). ctDNA identified recurrence with 100% specificity and 78% sensitivity. The NPV and PPV were 91% and 100%. PET had 78% sensitivity but only 68% specificity with 86% NPV, and 54% PPV. Based on our data, ctDNA can be an excellent adjunct test for posttreatment PET and can help guide physicians in cases where PET results are inconclusive and difficult to interpret.

Abstract 4995: Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer

Abstract Metastasis-ablative radiotherapy is a new therapeutic approach that prolongs survival in patients with advanced cancers. Tumour irradiation can elicit an immunogenic cell death resulting in the expansion of tumour-reactive T cells and eradication of both irradiated and distant non-irradiated metastases, referred to as the “abscopal effect”. This abscopal response, nevertheless, is observed in a minority of patients suggesting uncharacterized mechanisms that prevent robust systemic anti-tumor immune response. Tumour-derived extracellular vesicles (TdEVs) have recently emerged as mediators of antitumor immunity but their immunomodulatory role in response to radiotherapy remains largely unknown. Recent clinical studies by our lab have demonstrated that circulating levels of tumour-derived extracellular vesicles (tdEVs) are elevated in response to radiotherapy and high tdEV concentrations are associated with reduced levels of peripheral cytotoxic CD8+ T cells and higher risk of disease recurrence in advanced prostate cancer. Based on our findings, we hypothesize that radiotherapy induces the release of tumor-derived EVs that suppress anti-tumor immunity. Prostate cancer cells (PC3 and DU145) were irradiated with clinically used doses of ionizing radiation (20Gy x 1 or 10Gy x 3 fractions) and tdEVs were co-cultured with human CD8+ T cells to measure their proliferation and cytotoxic activity. Increased levels of tdEVs were released by tumour cells treated with radiotherapy. A higher frequency of impaired T cell cytotoxic activity and a reduction in CD8 T cell proliferation was found in the 10Gy x 3 radiation regimen. Proteomic analysis and western blot showed an increased expression of the immune checkpoint molecule B7-H3 on the tumour cell surface and tdEVs in response to radiotherapy. While coculture of CD8 T cells with B7-H3 depleted tdEVs led to recovery of T-cell cytotoxic ability, overexpression of the B7-H3 in tdEVs inhibited cytotoxic activity. This study provides a rationale for future studies in which we will test the immune-mediated effects of radiotherapy-induced tdEVs in immunocompetent mouse models and investigate B7-H3 blockade as a therapeutic approach to boost abscopal response in the treatment of advanced prostate cancer. Citation Format: Chisom J. Uzendu, Yohan Kim, Roxane R. Lavoie, Haidong Dong, Sean Park, Fabrice Lucien-Matteoni. Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4995.

Predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa squamous cell lung cancer: A retrospective analysis.

Lung cancer (LC) is a global medical, social and economic problem and is one of the most common cancers and the leading cause of mortality from malignant neoplasms. LC is characterized by an aggressive course, and in the presence of disease recurrence risk factors, patients, even at an early stage, may be indicated for adjuvant therapy to improve survival. However, combined treatment does not always guarantee a favorable prognosis. In this regard, establishing predictors of LC recurrence is highly important both for determining the optimal treatment plan for the patients and for evaluating its effectiveness. To establish predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa lung squamous cell carcinoma (LSCC). A retrospective case-control cohort study included 69 patients with LSCC who underwent radical surgery at the Orenburg Regional Clinical Oncology Center from 2009 to 2018. Postoperatively, all patients received adjuvant chemotherapy. Histological samples of the resected lung were stained with Mayer's hematoxylin and eosin and examined under a light microscope. Univariate and multivariate analyses were used to identify predictors associated with the risk of disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with a high risk of disease recurrence and those with a low risk of disease recurrence. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. Differences were considered to be significant at P < 0.05. The following predictors of a high risk of disease recurrence in patients with stage IIb-IIa LSCC were established: a low degree of tumor differentiation [odds ratio (OR) = 7.94, 95%CI = 1.08-135.81, P = 0.049]; metastases in regional lymph nodes (OR = 5.67, 95%CI = 1.09-36.54, P = 0.048); the presence of loose, fine-fiber connective tissue in the tumor stroma (OR = 21.70, 95%CI = 4.27-110.38, P = 0.0002); and fragmentation of the tumor solid component (OR = 2.53, 95%CI = 1.01-12.23, P = 0.049). The area under the curve of the predictive model was 0.846 (95%CI = 0.73-0.96, P < 0.0001). The sensitivity, accuracy and specificity of the method were 91.8%, 86.9% and 75.0%, respectively. In the group of patients with a low risk of LSCC recurrence, the 1-, 2- and 5-year disease-free survival (DFS) rates were 84.2%, 84.2% and 75.8%, respectively, while in the group with a high risk of LSCC recurrence the DFS rates were 71.7%, 40.1% and 8.2%, respectively (P < 0.00001). Accordingly, in the first group of patients, the 1-, 2- and 5-year overall survival (OS) rates were 94.7%, 82.5% and 82.5%, respectively, while in the second group of patients, the OS rates were 89.8%, 80.1% and 10.3%, respectively (P < 0.00001). The developed method allows us to identify a group of patients at high risk of disease recurrence and to adjust to ongoing treatment.

Outcomes of elderly patients with node-positive colon cancer: A multi-center population-based cohort study.

33 Background: Patients with stage III colon cancer are at high risk of recurrent disease. In this large population based cohort study we examined prognostic significance of chemotherapy and other clinical, pathological &amp; contextual variables that are associated with inferior outcomes in elderly patients with stage III colon cancer. Methods: Patients ≥ 70 years with stage III colon cancer diagnosed in Saskatchewan, a Canadian province, and underwent resection of the primary tumor during 2012-2018 were evaluated. A Cox proportional multivariate survival analysis was performed to determine factors correlated with overall survival (OS) and disease-free survival (DFS). Results: 404 eligible patients with median age of 79 yrs &amp; M:F of 1:1 were identified. 48% were ≥80 years, 60% were rural resident, 66% had ≥ 1 major comorbid illness, 34% had WHO performance status &gt;1, 14% has an ostomy formation, 46% had a T4 or N2 high-risk disease, and 50% had node positive to node harvested (NPNH) ratio of &gt;0.1. 43% patients received adjuvant chemotherapy. Median time to start chemo was 9 weeks. Patients who did not receive adjuvant chemotherapy were significantly older, had low performance status or experienced high rate of post-operative complications, high serum creatinine, low albumin, anemia, elevated WBC count and platelets. Median OS of all patients was 51 months (95%CI: 42.4-59.6), with estimated 5 &amp; 10-yr OS of 45% and 30%. Median DFS of entire cohort was 32 months (26.3-37.7) with 5 &amp; 10-yr DFS of 34% and 20%. Patients who received adjuvant chemotherapy had median OS of 106 months (83.8-128.5) vs. 30 months (23.4-36.6), p&lt;0.001 with 5 &amp; 10-yr OS of 64% and 49% vs. 31% and 19% (p&lt;0.001). Patients who received adjuvant chemotherapy had median DFS of 56 months (28.2-83.9) vs. 22 months (16.5-27.5), p&lt;0.001 with 5 &amp; 10-yr DFS of was 49% and 30% vs. 24% and 13% (p=&lt;0.001). The Cox-multivariate analysis revealed a past history of cancer, HR, 1.32 (1.03-1.72); ostomy, HR, 1.33 (1.02-1.74); NPNH ratio &gt;0.1, 1.34 (1.04-1.78); grade III tumor, 1.36 (1.04-1.78); WHO performance status &gt;1, HR, 1.38 (1.05-1.82); no adjuvant chemo, HR, 1.38 (1.03-1.85); high-risk stage III disease, HR, 1.39 (1.10-1.79), and baseline CEA &gt;5, HR, 1.75 (1.34-2.29), were independently correlated with DFS whereas past history of cancer, HR, 1.47 (1.12-1.94); ostomy, HR, 1.53 (1.16-2.03); NPNH ratio &gt;0.1, 1.51 (1.15-1.98); grade III tumor, 1.54 (1.16-2.04); WHO performance status &gt;1, HR, 1.42 (1.06-1.90); no adjuvant chemo, HR, 1.82 (1.32-2.50); high-risk stage III disease, HR, 1.60 (1.22-2.11), and CEA &gt;5, HR, 1.98 (1.50-2.61) were independently correlated with OS. Conclusions: In elderly patients with stage III colon cancer lack of adjuvant chemotherapy, poor performance status, T4 or N2 disease, grade III tumor, elevated baseline CEA, past history of a secondary cancer, elevate NPNH ratio &gt;0.1 and an ostomy formation correlate with inferior outcomes.

Advisory board resolution: The role of the adjuvant atezolizumab plus bevacizumab in patients with hepatocellular carcinoma at high risk of recurrence following surgical resection or ablation

MEETING DATE: July 7, 2023ITEMS ON THE AGENDA:1. The role of the adjuvant atezolizumab plus bevacizumab in patients with hepatocellular carcinoma (HCC) at high risk of recurrence following surgical resection or ablation. Profile of the patient who will benefit the most from this therapy.2. To evaluate the prospects for therapeutic options for patients with early HCC in Russia.Liver cancer remains a public health concern globally, with an increasing trend in the number of incident cases worldwide. Early, precise diagnosis and timely treatment contribute to the improvement in overall and relapse-free survival. It is important that the entire arsenal of local treatments (resection, ablation and liver transplantation) can be applied in cases when HCC is detected at a very early and early stage of the disease. Tumour recurrence after surgical treatment or ablation is a complex and underexplored problem in the treatment of patients with HCC. Many factors that can predict the risk of relapse after surgical treatment have been described: tumour size &gt;5 cm, &gt;3 foci, micro- or macrovascular (Vp1-2) invasion, poor degree of tumour differentiation (G3-4). Our advisory board tried to identify the most important risk factors for early relapse, and to determine the role and impact of the results of the first positive clinical trial focused on the issue of early HCC, IMbrave050: a phase 3 trial of adjuvant atezolizumab + bevacizumab vs active surveillance in patients with HCC at high risk of disease recurrence following resection or ablatio.

Occupational exposure to pesticides deregulates systemic cortisol levels in women with breast cancer and correlates with poor prognosis features.

Pesticides have been pointed out as hormone disruptors and may significantly affect the prognosis of hormone-dependent diseases such as breast cancer (BC). Here, we investigated the impact of occupational pesticide exposure on systemic cortisol levels in female rural workers diagnosed with BC. Occupational exposure was assessed by interviews with a standardized questionnaire. Plasma samples (112 from pesticide-exposed women and 77 from unexposed women) were collected in the afternoon, outside the physiological cortisol peak, and analyzed by a chemiluminescent paramagnetic immunoassay for the quantitative determination of cortisol levels in serum and plasma. The results from both groups were categorized according to patients' clinicopathological and exposure data. BC pesticide-exposed women presented higher levels of cortisol than the unexposed. Higher cortisol levels were also detected in the exposed group with more aggressive disease (triple-negative BC), with tumors over 2 cm, with lymph node metastases, and with high risk of disease recurrence and death. These findings demonstrated that there is an association between pesticide exposure and BC that affected cortisol levels and correlated to poor disease prognosis.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

EPH29 Estimating the Incidence and Characteristics of Female Patients in Norway With Early Breast Cancer Who Are at High Risk of Disease Recurrence

EPH29 Estimating the Incidence and Characteristics of Female Patients in Norway With Early Breast Cancer Who Are at High Risk of Disease Recurrence

A D-Dimer and Thrombin Generation-Based Risk Score Predicts Early-Disease Recurrence in a Prospective Cohort of 1,059 High-Risk Breast Cancer Patients

Introduction: Hemostatic biomarkers have been widely explored in different cancer types as possible predictors of specific cancer outcomes, including survival, malignant disease recurrence, and progression. Results from many small and single-center studies are promising, stimulating confirmatory data from large, prospective studies. In a large cohort of high-risk breast cancer patients enrolled in the prospective, observational, multicenter HYPERCAN study, we aim to establish whether prechemotherapy hemostatic levels can predict disease recurrence (DR). Methods: TheHYPERCAN study (ClinicalTrials.gov ID#NCT02622815) is a prospective, observational, multicenter study, specifically designed to evaluate the role of hemostatic biomarkers in relation to disease recurrence, disease progression, mortality response to therapy and thrombosis. Patients with surgically resected high-risk breast cancer enrolled between 2012 and 2019, from the HYPERCAN study were analyzed. Blood samples collected at enrollment, before starting anticancer treatment, were tested for thrombin generation (TG) by both the ST-Genesia system (STG-ThromboScreen reagent, with and without thrombomodulin) and the calibrated automated thrombogram (CAT) at 5 pM TF. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and proteins C and free protein S (FPS) were also measured. Outcome analyzed was early-DR (E-DR) within 2 years. Results: A total of 1,059 patients (15M/1,044F), mean age 53 years (SD±11) were analyzed. Breast conserving-resection was performed in 53% and mastectomy in 47% of patients. HER-2 expression was positive in 26% of tumor specimens. The most frequent molecular subtype was Luminal B HER2 negative (32%), followed by Luminal A (22%), Luminal B HER2 positive (19%), Triple negative (13%) and HER2 positive (8%). The largest proportion of tumors were classified as invasive ductal carcinoma, diagnosed in 86% of subjects. All patients were eligible for systemic adjuvant chemotherapy, and for receiving trastuzumab in case of HER-2 positivity. Within 2 years from enrollment, 53 (5.5 %) patients experienced an E-DR, 8 died, while 92 were lost at follow-up. E-DR patients were characterized by worse stage (IIIC), more frequently triple-negative, and less often Luminal-B/HER2-positive molecular subtypes (p&amp;lt;0.05). In addition, E-DR subjects were characterized by increased pre-chemotherapy levels of D-dimer (p=0.004), and peak of TG performed by both Genesia (p=0.001), with and without thrombomodulin, and by CAT (p&amp;lt;0.001) assays. The remaining coagulation parameters were not significantly different between the two groups. The competitive multivariable proportional hazard regression model, corrected for age and surgery status, identified D-dimer and TG peak (by both methods) as independent risk factors for E-DR. This model was internally validated by 1,000-bootstrapping resampling correction. A continuous risk score was therefore generated including D-dimer and TG, which provided a ROC AUC of 0.652 (p&amp;lt;0.001). By this score the patients were significantly stratified in a high- vs low-risk for E-DR (HR 23 vs 0%: Log-rank &amp;lt;0.001). Conclusions: In this large prospective cohort of surgically resected breast cancer patients at high-risk of DR, we could generate and internally validate a risk assessment model based on pre-treatment values of TG and D-dimer, able to identify those subjects at higher risk of DR in the first 2 years after tumor resection. This score, if externally validated, may help the clinical surveillance and serve as treatment guidance in patients with primary breast cancer that are at high risk of recurrence, avoiding overtreatment in those at low risk.

Role of Measurable Residual Disease (MRD) Testing for the Prediction of Late Relapses Following Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia

BACKGROUND: Measurable residual disease (MRD) before and/or shortly after allogeneic hematopoietic cell transplantation (HCT) is an independent indicator of high post-HCT relapse risk in acute myeloid leukemia (AML). However, many relapses, particularly among patients with MRD, occur within the first 3 months after allografting, and the role of MRD testing in the identification of patients at risk of relapses occurring at later times is unknown. METHODS: To address this uncertainty, we studied all adults ≥18 years with AML or MDS/AML based on 2022 International Consensus Classification criteria who received a first allograft while in first or second morphologic remission at a single institution between 4/2006 and 3/2023 and underwent MRD testing via multiparameter flow cytometry during the pre-HCT evaluation. In line with the performance characteristics of the assay, any detectable MRD was considered positive. RESULTS: One thousand two hundred and sixty-two patients with AML (n=1,112 [88%]) or MDS/AML (n=150 [12%])underwent allograft following myeloablative (n=732 [58%]) or non-myeloablative (n=530 [42%]) conditioning regimens. Of these, 260 (21%) tested positive for MRD during the pre-HCT evaluation. With a median follow-up of 60.6 (range: 1.9-196.3) months after HCT among survivors, there were 589 deaths, 381 relapses, and 259 NRM events contributing to the probability estimates for relapse, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) in this cohort. 239/1,262 patients (19%) experienced disease recurrence (n=181 [14%]) and/or death (n=89 [7%]) within the first 100 days after allografting. Relapse ( P&amp;lt;0.001) and death ( P=0.002) but not NRM ( P=0.29) before day +100 were more common among patients with pre-HCT MRD. Of patients alive without relapse at day +100, 93% (954 of 1,023) underwent bone marrow restaging studies between day 70 and 100 post-HCT. Among these 954 patients, 146 (15%) had MRD before HCT, whereas only 25 (3%) had MRD at day +70-100 testing. The latter had a significantly higher 3-year relapse risk (37% vs. 18%; P=0.002), and worse RFS (17% vs. 68%; P&amp;lt;0.001) OS (16% vs. 72%; P&amp;lt;0.001) and NRM (46% vs. 14%; P&amp;lt;0.001) relative to the 929 patients without MRD; for results of univariate regression models, see Table 1. Importantly, however, while 130 of the 146 patients (89%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were substantially worse compared to patients who tested negative for MRD before HCT and at day +70-100, with 3-year relapse risk of 38% vs. 15% ( P&amp;lt;0.001), 3-year RFS of 47% vs. 71% ( P&amp;lt;0.001), and 3-year OS of 53% vs. 75% ( P&amp;lt;0.001), whereas 3-year NRM estimates were similar (14% vs. 14% ( P=0.21). Qualitatively similar results were obtained when the cohort was restricted to patients with AML, and also when comparing patients undergoing myeloablative conditioning with those undergoing non-myeloablative conditioning, with a statistically significantly higher relapse risk and lower RFS and OS but not NRM for patients with MRD before HCT but no MRD at day +70-100 compared to those who tested negative for MRD before HCT and at day +70-100 (Table 1). CONCLUSION: For AML and MDS/AML patients alive without relapse at day +100 after allografting, MRD testing at day +70-100 post-HCT identifies patients at increased risk of relapse and worse survival, but only a small number of patients will test positive at this post-HCT timepoint. While a high proportion of patients with MRD before HCT will test negative for MRD at day +70-100, their outcomes are substantially inferior to patients without MRD both before and at day +70-100 after HCT. These data suggest that all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies, ideally in the setting of well-controlled clinical trials, given their high risk of disease recurrence regardless of the post-HCT MRD information.

Could a Risk-adapted Approach Support Shared Decision-making Regarding Eligibility for Adjuvant Pembrolizumab for Patients with Clear Cell Renal Cell Carcinoma at High Risk of Recurrence? A Multicentre Cohort Study

The KEYNOTE-564 randomised controlled trial showed a disease-free survival benefit of adjuvant pembrolizumab (aPZB) in comparison to placebo for patients with clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. Despite its recommendation by the European Association of Urology guidelines, the ultimate value of aPZB has recently been questioned. Arguably, patients who might benefit the most from aPZB are those whose probability of RCC recurrence outweighs their probability of dying from other causes over a reasonable timeframe after surgery. To assess the potential impact of this hypothesis on “eligibility” for aPZB, we queried our prospectively collected multi-institutional database for consecutive patients undergoing surgery for nonmetastatic renal masses (cT1–4 N0–1 M0) between 2015 and 2021 to identify ccRCC cases meeting the KEYNOTE-564 criteria. We stratified the patients using the risk-adapted model proposed by Stewart-Merrill et al (whereby stopping follow-up is warranted when the estimated risk of other-cause mortality [OCM] outweighs the estimated risk of RCC recurrence). Then we explored the proportion of patients whose follow-up could theoretically be stopped at 2, 5, 10, or 20 yr, for whom “eligibility” for aPZB might be more controversial. Overall, 1745 patients with ccRCC were included, of whom 419 (24%) met the KEYNOTE-564 criteria. The proportion of patients “not eligible” for aPZB because of higher probability of OCM than of RCC recurrence would have been 81%, 66%, 43%, and 29% at “recommended” follow-up of ≤2.0, ≤5, ≤10, and ≤20 yr, respectively. To the best of our knowledge, this is the first study providing insights to support shared decision-making regarding eligibility for aPZB for patients with nonmetastatic ccRCC with a focus on patient-related factors beyond tumour-driven prognostic scores. Patient summaryAn immunotherapy drug call pembrolizumab given after surgery for nonmetastatic kidney cancer may benefit some patients who have a high risk of disease recurrence, but it can have immune-related side effects. We found that comparing the risk of death from other causes and the risk of cancer recurrence could help in reducing overtreatment of patients who might not benefit from this drug.

Patterns of Recurrence of Cutaneous Melanoma: A Literature Review.

The incidence of melanoma has been dramatically increasing over the last decades. Melanoma is considered to have a high metastatic potential and it can progress via lymphatic vessels or through hematogenous metastasis. Different patterns of recurrence have been described, namely, local, satellite, and in transit metastasis (LCIT), lymphatic metastasis, and systemic metastasis. With a more advanced melanoma stage at diagnosis, there is a higher risk for systemic metastasis in comparison to LCIT; in contrast, early-stage melanoma tends to recur more frequently as LCIT and less commonly as systematic metastasis. The aim of this review was to summarize the patterns of recurrence of cuta-neous melanoma, giving the clinician a practical summary for diagnosis, prognosis, and surveillance. There is a knowledge gap of the common patterns of recurrence that needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies as well as patient counseling.

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition.

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

Cost-effectiveness analysis of abemaciclib with endocrine therapy (ET) versus ET alone for HR+, HER2-, node-positive, high-risk early breast cancer in Italy.

Abemaciclib was recently approved by the European Medicines Agency in combination with adjuvant endocrine therapy (ET) for adult patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive early breast cancer (EBC) at high risk of recurrence. To evaluate the cost-effectiveness of abemaciclib plus ET vs. ET alone in patients with HR+, HER2-, node-positive EBC at high risk of disease recurrence, from the Italian healthcare system perspective. A cohort state transition model was developed with five states: invasive disease-free survival (IDFS), nonmetastatic recurrence, remission, metastatic recurrence, and death. The analysis had a time horizon of 30years. Individual patient-level data from the monarchE trial (NCT03155997) were used to generate IDFS estimates. Resource use included drug acquisition/administration, best supportive care, terminal care, adverse events, hospitalization, post-progression therapy, and associated resource use in the metastatic disease health state. Health state utilities were derived from monarchE patient-level data and other sources, applying Italian tariffs where feasible. The estimated total discounted costs (€39,249 vs. €16,806; difference: €22,443) and quality-adjusted life years (QALYs) (11.49 vs. 10.50; difference: 0.99) were higher for abemaciclib plus ET compared with ET alone. The incremental cost-effectiveness ratio was €22,651 per QALY gained. The likelihood of abemaciclib plus ET being cost-effective vs. ET alone was 99% at a willingness-to-pay threshold of €30,000 per QALY gained. Abemaciclib plus ET is a cost-effective treatment option vs. ET alone for those with HR+, HER2- node-positive EBC at high risk of recurrence in Italy.